Are predatory brain immune cells eating nerve cells in Amyotrophic lateral sclerosis (ALS)?

Good news!

"Highlights

• Salk scientists discover that central nervous system-resident immune cells called microglia use TAM receptors (discovered by study senior author Greg Lemke in 1991) to eat specific nerve cells in mouse model of ALS
• The study is the first to show TAM receptors can be used to kill living nerve cells
• The insights contribute to ongoing efforts to harness TAM receptors in clinical settings to treat cancers, autoimmune disorders, and more

...

Neurons are often the center of attention in brain and neurodegeneration research, but other cells in the central nervous system are important, too. Recent studies have shown microglia, which are immune cells specific to the brain and spinal cord, are very active during human ALS. The question is: Why? ...

Active microglia can be easily identified in research by assessing their expression of TAM receptors. ... discovered this family of proteins, which are critical bridges between the immune system and the rest of the body, more than three decades ago. ...

To determine whether the TAM system was the link between microglia activation and motor neuron death in ALS, the ... researchers started with the most widely used mouse model of ALS, called SOD1. These mice express a mutant SOD1 protein that causes ALS in people.

They first found that many motor neurons had been eaten in the spinal cords of SOD1 mice. The levels of TAM proteins were also elevated in these mice, particularly Axl and Mer.

Looking closer at the motor neurons, the scientists noticed those “eat me” signs, which are little molecules called phosphatidylserine, were being displayed on cells when they shouldn’t be. From there, the TAM system springs into action, guiding microglia to their next meal: a live neuron.

The natural next question ... is “what happens when we eliminate Axl and Mer?” Without these two TAM family proteins, the mice got sicker faster but lived longer. ...

“When we looked at how many motor neurons mice without Axl and Mer had, compared to mice with Axl and Mer, we found losing the TAM proteins meant preserving muscle controls.” ..."

From the abstract:

"Activation of microglia is a prominent feature of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease that leads to the death of motor neurons.

A key component of this activation is elevated expression of the TAM receptor tyrosine kinases Axl and Mer (gene name Mertk).

Here we show that germline and microglial-restricted inactivation of the Axl and Mertk genes in the SOD1G93A mouse model of ALS leads to an extension of lifespan, which is tied to the preservation of cholinergic motor neurons and neuromuscular synapses.

Also elevated on SOD1G93A neuronal surfaces is the essential TAM co-ligand phosphatidylserine, a potent ‘eat-me’ signal through which apoptotic cells are engulfed by microglia.

Correspondingly, we find that microglial lysosomes are filled with the remains of cholinergic neurons in the SOD1G93A spinal cord, whereas this accumulation is markedly reduced in the SOD1G93AAxl-/-Mertk-/- cord.

Together, these results suggest that microglia phagocytically kill living neurons, and thereby hasten death in ALS."

Are predatory brain immune cells eating nerve cells in ALS? – Salk Institute "Salk Institute scientists discover central nervous system immune cells find and kill specific nerve cells in the spinal cords of mice with late-stage ALS, exacerbating the condition; findings could be harnessed in cancer and autoimmune therapy innovation efforts"

Microglia deploy TAM receptors to kill motor neurons in a mouse model of amyotrophic lateral sclerosis (open access, but still in press)

Microglia (green) contain the remnants of motor neurons (purple) inside microglial lysosomes (yellow).

Headbutting gives goats brain damage. Really!

Why should it be different from human beings? Will these animals become a model to study human neurodegenerative disorders?

From the abstract:

"Traumatic brain injury (TBI) is a characteristic feature of neurodegenerative diseases such as Alzheimer’s disease and chronic traumatic encephalopathy. Small animal models have been used to establish clinically relevant biomarkers of neuropathology, however, they show significant anatomical differences from humans and are affected by artificial experimental manipulations, making them often unsuitable for longitudinal study of repetitive mild TBI. There is a need for more diverse and translationally relevant animal models to better understand disease onset and development.

Building on a previous study of neuropathology in headbutting bovids in the wild, this pilot study investigated whether freely headbutting domestic goats, which naturally engage in low-intensity, high-frequency head impacts, accumulate measurable biomarkers of neurodegeneration in cerebrospinal fluid (CSF) and brain tissue. Over a six-month period, three male goats (Capra hircus) were allowed to freely headbutt under continuous video surveillance.

Monthly CSF samples were collected, and concentrations of key neurodegeneration biomarkers were measured via multiplex immunoassays, including amyloid-β peptides (Aβ40, Aβ42), total and phosphorylated tau (tTau and pTau), glial fibrillary acidic protein (GFAP), S100 calcium-binding protein B (S100B), and neurofilament M (NF-M). Imaging studies were completed for non-invasive assessment of glucose metabolism ([18F]-FDG) and neuroinflammation via translocator protein (TSPO, [18F]DPA-714).

Postmortem immunohistochemistry was conducted on prefrontal cortical tissues using antibodies targeting pTau, GFAP, and S100B. Head impact kinematics were quantified using horn-mounted accelerometer and inclinometer sensors that recorded linear acceleration, rotational velocity, and head orientation during naturally occurring headbutting events.

Several notable trends were observed. Phosphorylated tau as well as reactive astrocytes were detected in the brain tissue, mirrored by elevated GFAP detected in the CSF. PET TSPO did not illustrate a significant signal, however, PET FDG revealed frontal-dominant activity in all goats, and one with asymmetrical activation.

Overall, the goats sustained 5,000-7,000 head impacts each over six months. Accelerometer measurements recorded forces up to 388 N and peak acceleration up to 16.5 g.

This multi-modal observational study is the first to characterize neurodegeneration biomarkers and kinematics in headbutting goats.

Even at one year old, the combination of pTau and gliosis in both the brain tissue and CSF indicates that the goat’s repetitive head impacts begin to show neurodegenerative consequences early in life.

Likely, the severity of these consequences increases with headbutts and age, eventually resulting in chronic neurodegeneration. This system shows promise as a large-animal model for the longitudinal study of the onset and progression of neurodegenerative disease."

ScienceAdviser

Headbutting goats self-inflict traumatic brain injury (preprint, open access)

Dolphins may develop an Alzheimer’s-type brain disease similar to humans due to climate change? Really!

Did we not know how smart dolphins are since the famous Flipper TV show series of the 1960s?

This could be very interesting! How about e.g. elephants?

I am seriously troubled that the study resorts to climate change as an explanation! This mixup is not helpful! It is muddying the water (pardon my pun)! This could indicate a serious bias on part of the involved scientists.

"Scientists say dolphins may develop an Alzheimer’s-type brain disease similar to humans, which could explain why some are found disoriented, stranded far from home."

From the abstract:

"Climate warming [???] is one factor increasing the severity of harmful algal blooms (HABs). Innovative exposure models are needed to understand how HABs affect brain health. Here, we examined HAB exposure on the brain transcriptome of dolphins found stranded in Florida’s Indian River Lagoon.

We report the neurotoxin 2,4-diaminobutyric acid (2,4-DAB) is 2900 times more concentrated in dolphin brains during bloom seasons compared to non-bloom seasons.

The same dolphins show 536 differentially expressed genes whose enrichment reveal impairment in GABAergic synapses, basement membrane alteration, and Alzheimer’s disease (AD) risk factors that increase with each subsequent season. 

Dolphins also display concurrent AD-like neuropathological changes and elevated AD gene expression with 2,4-DAB exposure.

Our study demonstrates disproportionate seasonal exposure to 2,4-DAB increases AD signatures in the brain transcriptome.

As our climate warms [???], HABs will continue to intensify. Understanding the impact of HAB exposures will help to identify populations at risk for neurological illnesses."

 

Friday, October 3, 2025 - Join The Flyover

Do stranded dolphins have Alzheimer's disease? (original news release)

Alzheimer’s disease signatures in the brain transcriptome of Estuarine Dolphins (open access)

Fig. 5: Alzheimer’s disease-like neuropathological changes in Indian River Lagoon dolphins.

A biotech company says it put dopamine-making cells into people’s brains to treat Parkinson's Disease

Good news! This is my second blog post today on new treatments for Parkinson's.

"In an important test for stem-cell medicine, a biotech company says implants of lab-made neurons introduced into the brains of 12 people with Parkinson’s disease appear to be safe and may have reduced symptoms for some of them.

The added cells should produce the neurotransmitter dopamine, a shortage of which is what produces the devastating symptoms of Parkinson’s, including problems moving.  ..."

A biotech company says it put dopamine-making cells into people’s brains | MIT Technology Review The experiment to treat Parkinson’s is a critical early test of stem cells’ potential to tackle serious disease.

BlueRock’s Phase I study with bemdaneprocel in patients with Parkinson’s disease meets primary endpoint

Mix of existing medications Alleviates Parkinson's Symptoms In New Study

Good news! Sometimes mixing medications improves symptoms.

"Pharma Two B has developed a once-a-day injection that combines two existing Parkinson’s disease (PD) treatments, pramipexole and rasagiline, at low doses that are not commercially available.

The firm’s recent clinical trial compared the effects of its P2B001 therapy against conventional treatments in over 500 patients over the course of 12 weeks.

It found that the treatment not only significantly improved the motor symptoms and daily function of the patients, but resulted in fewer side effects than other treatments. ..."

Revolutionary Jab Alleviates Parkinson's Symptoms In New Study An Israeli pharma company has found that its jab to alleviate the symptoms of patients with early Parkinson’s disease is more effective than those currently on the market.

Pharma Two B to Present Additional Phase 3 Positive Results of P2B001, a once-daily, fixed-dose combination of low-dose pramipexole and low-dose rasagiline, at 2023 International Congress of Parkinson’s Disease and Movement Disorders

Study reveals insights into link between genetic mutation and Parkinson’s

Good news! Towards defeating those dreaded neurodegenerative diseases!

"... In a new study, ... researchers reveal new insights into this question, finding that the LRRK2 gene can suppress activity in lysosomes, microscopic organelles that play a key role in breaking down and disposing of cellular waste. ...

LRRK2 genes can also reduce activity of macrophages and microglia, specialized cells that act as the body’s scavengers, clearing away misfolded proteins, cell debris, dead cells, and pathogens, the researchers found. In the brain, microglia help protect neurons from threats posed by these excess materials. ...

The loss of such protective functions as a result of LRRK2 genetic mutations could explain the link between LRRK2 and Parkinson’s disease, the researchers say. Furthermore, outside the brain, the suppression of lysosomes by LRRK2 in macrophages may help explain links between LRRK2 and other diseases including leprosy and Crohn’s disease. ...

“LRRK2 acts like a brake on a garbage truck and if the brake is too strong it limits the ability of these scavenger cells to eliminate damaging material,”  ..."

From the significance and abstract:

"Significance

This study defines a homeostatic mechanism that allows macrophages and microglia to match the degradative activity of their lysosomes to ongoing changes in cellular demand. It shows that the leucine-rich repeat kinase 2 (LRRK2) protein suppresses lysosome degradative activity by inhibiting the expression and nuclear localization of the MiT-TFE family of transcription factors that control the expression of multiple genes that encode lysosome proteins. It further demonstrates that a Parkinson’s disease mutation that hyperactivates LRRK2 kinase activity limits the degradative activity of lysosomes more strongly. These findings support a model wherein LRRK2 protects cells from excessive lysosome degradative activity and suggest that overactivation of this pathway may increase Parkinson’s disease risk by limiting the degradative activity of lysosomes.

Abstract

Cells maintain optimal levels of lysosome degradative activity to protect against pathogens, clear waste, and generate nutrients. Here, we show that LRRK2, a protein that is tightly linked to Parkinson’s disease, negatively regulates lysosome degradative activity in macrophages and microglia via a transcriptional mechanism. Depletion of LRRK2 and inhibition of LRRK2 kinase activity enhanced lysosomal proteolytic activity and increased the expression of multiple lysosomal hydrolases. Conversely, the kinase hyperactive LRRK2 G2019S Parkinson’s disease mutant suppressed lysosomal degradative activity and gene expression. We identified MiT-TFE transcription factors (TFE3, TFEB, and MITF) as mediators of LRRK2-dependent control of lysosomal gene expression. LRRK2 negatively regulated the abundance and nuclear localization of these transcription factors and their depletion prevented LRRK2-dependent changes in lysosome protein levels. These observations define a role for LRRK2 in controlling lysosome degradative activity and support a model wherein LRRK2 hyperactivity may increase Parkinson’s disease risk by suppressing lysosome degradative activity."

Study reveals insights into link between genetic mutation and Parkinson’s | YaleNews In a new study, ... researchers reveal new insights into the role of the LRRK2 gene in triggering the devastating neurodegenerative disease.

LRRK2 suppresses lysosome degradative activity in macrophages and microglia through MiT-TFE transcription factor inhibition (open access)

Fig. 2 LRRK2 negatively regulates the levels of multiple lysosomal proteins in human iPSC-derived macrophages.

Erroneous genetic sequences identified for the first time in specific cells of ALS and frontotemporal dementia patients

Good news! Are we finally zeroing in on discovering the genetics behind some of the severe neurodegenerative diseases!

Perhaps, there is hope for the senile, demented, and corrupted 46th President (pardon my bad joke)!

"Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases with mean survival of 2-5 years and 6-8 years, respectively. ...

In some cases, the same genetic mutations occur in both. One of those mutations is a repetitive expansion in the DNA of a gene called C9ORF72. ... One of the significant changes that happens in the majority of cases of ALS and around half of the cases of FTD, is when a protein called TAR DNA binding protein (TDP-43) clumps together and stops working correctly. When TDP-43 doesn’t function properly, it puts incorrect genetic instructions into the RNA, which are called “cryptic exons.”
Now, a team of scientists ... have detected these cryptic exons in specific brain cells from ALS and FTD patients carrying a mutation in the C9ORF72 gene. ..."

From the abstract:

"The C9ORF72-linked diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by the nuclear depletion and cytoplasmic accumulation of TAR DNA-binding protein 43 (TDP-43). Recent studies have shown that the loss of TDP-43 function leads to the inclusion of cryptic exons (CE) in several RNA transcript targets of TDP-43. Here, we show for the first time the detection of CEs in a single-nuclei RNA sequencing (snRNA-seq) dataset obtained from frontal and occipital cortices of C9ORF72 patients that phenotypically span the ALS-FTD disease spectrum. We assessed each cellular cluster for detection of recently described TDP-43-induced CEs. Transcripts containing CEs in the genes STMN2 and KALRN were detected in the frontal cortex of all C9ORF72 disease groups with the highest frequency in excitatory neurons in the C9ORF72-FTD group. Within the excitatory neurons, the cluster with the highest proportion of cells containing a CE had transcriptomic similarities to von Economo neurons, which are known to be vulnerable to TDP-43 pathology and selectively lost in C9ORF72-FTD. Differential gene expression and pathway analysis of CE-containing neurons revealed multiple dysregulated metabolic processes. Our findings reveal novel insights into the transcriptomic changes of neurons vulnerable to TDP-43 pathology."

Erroneous genetic sequences identified for the first time in specific cells of ALS and frontotemporal dementia patients | AZBio Gene splicing defect known as “cryptic exons” detected using single-nuclei RNA sequencing

Cryptic exon detection and transcriptomic changes revealed in single-nuclei RNA sequencing of C9ORF72 patients spanning the ALS-FTD spectrum (open access)

Fig. 1 Detection of STMN2 and KALRN cryptic exons in single-nuclei sequencing data from subjects with C9-ALS, C9-ALS-FTD, and C9-FTD.

Tracking Your Tears In Early Test For Alzheimer's And Parkinson's

Good news! Amazing stuff! Confirms one more time that Israel is a hotbed for innovation!

Cry it all out!

"... Early detection is crucial for both diseases, however, as treatments to slow the progression of both are more successful the sooner they are administered. ...

LacriScan diagnosis test uses tears, which are both easily accessible and intrinsically linked to the central nervous system.  

Because of these two factors, “we can identify a component in the tears that reflects processes in the brain, and in the early stages before the patient with Alzheimer’s or Parkinson’s develops clinical symptoms,” ...

The diagnostic process itself is based on the commonly used Schirmer Test that monitors tear production, which involves inserting a paper strip inside the lower eyelid to gather the fluid. 

Once collected, the tears undergo ... patented analysis, looking for biochemical markers ... of the two diseases. The two ailments ... “have a shared identity. ...
... was already working with the use of tears as a diagnosis tool during his research into a rare genetic disorder called NGLY1 deficiency, which has less than 100 cases worldwide, but five instances in the same family in northern Israel. And one of the symptoms of NGLY1 deficiency is alacrima, or abnormal tear production. ” ...
While similar tests for neurological diseases using tears have already been developed, ... that his method differs in two ways: a more sensitive test response and analysis that looks for multiple brain chemical markers of the two diseases. ..."

Tracking Your Tears In Early Test For Alzheimer's And Parkinson's An Israeli researcher has patented a way of using a patient’s tears to diagnose Alzheimer’s and Parkinson’s – the two most common neurodegenerative diseases in the world – in their pre-symptom stages. 

Anti-ageing protein klotho injection boosts monkeys’ memories

Here is a business proposition! 😊

"Injecting ageing monkeys with a ‘longevity factor’ protein can improve their cognitive function, a study reveals. ... could lead to new treatments for neurodegenerative diseases.

It is the first time that restoring levels of klotho — a naturally occurring protein that declines in our bodies with age — has been shown to improve cognition in a primate. Previous research on mice had shown that injections of klotho can extend the animals’ lives and increases synaptic plasticity — the capacity to control communication between neurons, at junctions called synapses. ..."

From the abstract:

"Cognitive dysfunction in aging is a major biomedical challenge. Whether treatment with klotho, a longevity factor, could enhance cognition in human-relevant models such as in nonhuman primates is unknown and represents a major knowledge gap in the path to therapeutics. We validated the rhesus form of the klotho protein in mice showing it increased synaptic plasticity and cognition. We then found that a single administration of low-dose, but not high-dose, klotho enhanced memory in aged nonhuman primates. Systemic low-dose klotho treatment may prove therapeutic in aging humans."

Anti-ageing protein injection boosts monkeys’ memories First primate studies to show cognitive benefits of the protein klotho could be a step towards clinical applications.

Longevity factor klotho enhances cognition in aged nonhuman primates (open access)

New research shows astrocytes are key to swaying the pendulum in Alzheimer's disease progression

Good news!

"... By testing the blood of more than 1,000 cognitively unimpaired elderly people with and without amyloid pathology, the Pitt-led research team found that only those who had a combination of amyloid burden and blood markers of abnormal astrocyte activation, or reactivity, would progress to symptomatic Alzheimer's in the future, a critical discovery for drug development aimed at halting progression. ...
Inclusion of astrocyte reactivity markers, such as GFAP, in the panel of diagnostic tests will allow for improved selection of patients who are likely to progress to later stages of Alzheimer's and, therefore, help fine-tune selection of candidates for therapeutic interventions who are more likely to benefit. ..."

From the abstract (this one is not easy to interpret):

"An unresolved question for the understanding of Alzheimer’s disease (AD) pathophysiology is why a significant percentage of amyloid-β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash Aβ effects in pathological tau phosphorylation. Here, in a biomarker study across three cohorts (n = 1,016), we tested whether astrocyte reactivity modulates the association of Aβ with tau phosphorylation in CU individuals. We found that Aβ was associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity (Ast+). Cross-sectional and longitudinal tau–positron emission tomography analyses revealed an AD-like pattern of tau tangle accumulation as a function of Aβ only in CU Ast+ individuals. Our findings suggest astrocyte reactivity as an important upstream event linking Aβ with initial tau pathology, which may have implications for the biological definition of preclinical AD and for selecting CU individuals for clinical trials."

New research shows astrocytes are key to swaying the pendulum in Alzheimer's disease progression

Astrocyte reactivity influences amyloid-β effects on tau pathology in preclinical Alzheimer’s disease

Fig. 1: Astrocyte reactivity influences Aβ-dependent tau phosphorylation.

40 Hz vibrations reduce Alzheimer's pathology, symptoms in mouse models

Good news! So simple! Shake it, don't break it! 😊

"Evidence that non-invasive sensory stimulation of 40 Hz gamma frequency brain rhythms can reduce Alzheimer's disease pathology and symptoms, already shown with light and sound by multiple research groups in mice and humans, now extends to tactile stimulation. A new study by MIT scientists shows that Alzheimer's model mice exposed to 40 Hz vibration an hour a day for several weeks showed improved brain health and motor function compared to untreated controls. ..."

From the abstract:

"The risk for neurodegenerative diseases increases with aging, with various pathological conditions and functional deficits accompanying these diseases. We have previously demonstrated that non-invasive visual stimulation using 40 Hz light flicker ameliorated pathology and modified cognitive function in mouse models of neurodegeneration, but whether 40 Hz stimulation using another sensory modality can impact neurodegeneration and motor function has not been studied. Here, we show that whole-body vibrotactile stimulation at 40 Hz leads to increased neural activity in the primary somatosensory cortex (SSp) and primary motor cortex (MOp). In two different mouse models of neurodegeneration, Tau P301S and CK-p25 mice, daily exposure to 40 Hz vibrotactile stimulation across multiple weeks also led to decreased brain pathology in SSp and MOp. Furthermore, both Tau P301S and CK-p25 mice showed improved motor performance after multiple weeks of daily 40 Hz vibrotactile stimulation. Vibrotactile stimulation at 40 Hz may thus be considered as a promising therapeutic strategy for neurodegenerative diseases with motor deficits."

40 Hz vibrations reduce Alzheimer's pathology, symptoms in mouse models (secondary source)

40 Hz vibrations reduce Alzheimer’s pathology, symptoms in mouse models (primary source MIT) Tactile stimulation improved motor performance, reduced phosphorylated tau, preserved neurons and synapses and reduced DNA damage, a new study shows

Vibrotactile stimulation at gamma frequency mitigates pathology related to neurodegeneration and improves motor function (open access)

An enlarged detail from a figure in the paper highlights reductions in phosphorylated tau (magenta) in primary somatosensory cortical neurons in Tau P301S model mice treated with 40 Hz tactile stimulation (right). An image from an untreated control is on the left.

Gut bacteria linked to Parkinson's, paves way for targeted treatment

Good news! 

However, the new study only seems to confirm the linkage, but does not explain the it. Apparently, more studying needs to be done!

There might be a flaw in this study: As healthy subjects the researchers selected the health spouses of PD patients. Well that certainly raises some questions given the intimate relationship between patient and spouse.

"... Clumped alpha-syn has also been found in the gut, and it’s thought that a gut-based pathogen may cause the aggregation, which then travels to the brain.

In an effort to better understand what causes PD, researchers ... have closely examined the role that a species of bacteria – Desulfovibrio (DSV) – might play.

They’d looked at the link between DSV and PD in 2021 when they found the bacteria were more prevalent in people with the disease. They also found that, in people with PD, having more of these bacteria correlated with the severity of symptoms seen.

However, in the previous study, the way DSV contributed to the development of PD was not explored. Now, the researchers turned to science’s favorite worm, Caenorhabditis elegans (C. elegans), to examine whether DSV strains contributed to alpha-syn aggregation and PD. ..."

"... The study also found that Desulfovibrio strains isolated from healthy individuals do not cause α-synuclein aggregation to the same degree. In contrast, the aggregates caused by the Desulfovibrio strains in patients with Parkinson’s diseases were also larger. ..."

From the abstract:

"Introduction: The aggregation of the neuronal protein alpha-synuclein (alpha-syn) is a key feature in the pathology of Parkinson’s disease (PD). Alpha-syn aggregation has been suggested to be induced in the gut cells by pathogenic gut microbes such as Desulfovibrio bacteria, which has been shown to be associated with PD. This study aimed to investigate whether Desulfovibrio bacteria induce alpha-syn aggregation.

Methods: Fecal samples of ten PD patients and their healthy spouses were collected for molecular detection of Desulfovibrio species, followed by bacterial isolation. Isolated Desulfovibrio strains were used as diets to feed Caenorhabditis elegans nematodes which overexpress human alpha-syn fused with yellow fluorescence protein. Curli-producing Escherichia coli MC4100, which has been shown to facilitate alpha-syn aggregation in animal models, was used as a control bacterial strain, and E. coli LSR11, incapable of producing curli, was used as another control strain. The head sections of the worms were imaged using confocal microscopy. ...

Results and Discussion: Statistical analysis revealed that worms fed Desulfovibrio bacteria from PD patients harbored significantly more (P<0.001, Kruskal-Wallis and Mann-Whitney U test) and larger alpha-syn aggregates (P<0.001) than worms fed Desulfovibrio bacteria from healthy individuals or worms fed E. coli strains. In addition, during similar follow-up time, worms fed Desulfovibrio strains from PD patients died in significantly higher quantities than worms fed E. coli LSR11 bacteria (P<0.01). These results suggest that Desulfovibrio bacteria contribute to PD development by inducing alpha-syn aggregation."

Gut bacteria linked to Parkinson's, paves way for targeted treatment A new study has found that a species of gut bacteria cause the destructive nerve cell ‘clumps’ that are a hallmark of Parkinson’s disease. The discovery opens the door to the development of targeted treatments for this debilitating disease.

Researchers discover a potential cause of Parkinson’s disease Researchers at the University of Helsinki have demonstrated that certain strains of Desulfovibrio bacteria are the likely cause of Parkinson’s disease in most cases. The study enables the screening of the carriers of Desulfovibrio strains and the removal of the bacteria from the gut.

Desulfovibrio bacteria enhance alpha-synuclein aggregation in a Caenorhabditis elegans model of Parkinson’s disease (open access)

Figure 1 Head section of C. elegans worms fed with E. coli controls and Desulfovibrio bacteria from patients with Parkinson’s disease and healthy individuals.

Study challenges the theory that Alzheimer’s disease is primarily driven by amyloid plaques

Good news!

"... The researchers found that the man had a mutation in a gene coding for a protein called reelin, which is associated with brain disorders including schizophrenia and autism. Little is known about reelin’s role in Alzheimer’s, so the researchers genetically engineered mice with the same mutation. In mice, the mutated form of reelin caused the tau protein to be chemically modified, limiting its ability to cluster around neurons. The study challenges the theory that Alzheimer’s disease is primarily driven by amyloid plaques ...
The fact that the man stayed mentally healthy for so long despite the many amyloid plaques in his brain suggests that Alzheimer’s is more complicated ...
there could be multiple subtypes of Alzheimer’s, only some of which are driven by amyloid ..."

From the abstract:

"We characterized the world’s second case with ascertained extreme resilience to autosomal dominant Alzheimer’s disease (ADAD). Side-by-side comparisons of this male case and the previously reported female case with ADAD homozygote for the APOE3 Christchurch (APOECh) variant allowed us to discern common features. The male remained cognitively intact until 67 years of age despite carrying a PSEN1-E280A mutation. Like the APOECh carrier, he had extremely elevated amyloid plaque burden and limited entorhinal Tau tangle burden. He did not carry the APOECh variant but was heterozygous for a rare variant in RELN (H3447R, termed COLBOS after the Colombia–Boston biomarker research study), a ligand that like apolipoprotein E binds to the VLDLr and APOEr2 receptors. RELN-COLBOS is a gain-of-function variant showing stronger ability to activate its canonical protein target Dab1 and reduce human Tau phosphorylation in a knockin mouse. A genetic variant in a case protected from ADAD suggests a role for RELN signaling in resilience to dementia."

How one man's rare Alzheimer’s mutation delayed the onset of disease Genetic resilience found in a person predisposed to early-onset dementia could potentially lead to new treatments.

Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man (open access)

Fig. 1: PET imaging of the RELN-COLBOS (H3447R) carrier

Gene therapy could help restore vision lost to degenerative disease

Good news!

"... The team found a way to activate 'dormant' cells in the retina to reprogram them into what are called induced neuron cells, which could then be converted into new light-sensing cells to restore lost vision. ...
In doing so, the team identified a pair of transcription factors called Ikzf1 and Ikzf4, which can be expressed in Müller cells to convert them into retinal neurons. These could in turn be coaxed to replace key light-sensing cells. Other studies have found promising results doing similar things with other transcription factors. ..."

"... Although various approaches such as gene therapy exist that offer hope of slowing or blocking the progression of photoreceptor cell loss, these techniques cannot restore lost cells and are therefore not useful for patients at the advanced stages of the disease. ...
In an approach that circumvents the need for transplantation, ... team found a way to reactivate dormant cells in the retina and transform them into neural-like cells that could ultimately be used to replace cells lost in retinal degeneration. ..."

From the significance and abstract:

"Significance

The sequential production of cell types during neural development is controlled by temporal identity transcription factors, and heterochronic expression of these factors in progenitors reprograms developmental potential and promotes the production of temporally inappropriate cell types. It remains unknown, however, whether temporal factors can reprogram terminally differentiated cells. Here, we report that the combined expression of early temporal identity factors Ikzf1 and Ikzf4, homologs of Drosophila hunchback (hb), can convert uninjured retinal glia into neuron-like cells. Furthermore, we show that Ikzf1/Ikzf4 can reprogram fibroblasts into induced neurons (iNs) by altering chromatin accessibility and enabling a neuronal gene expression program. This work uncovers the reprogramming ability of temporal identity factors, opening the door to cell therapy approaches for neurodegenerative diseases.

Abstract

Temporal identity factors are sufficient to reprogram developmental competence of neural progenitors and shift cell fate output, but whether they can also reprogram the identity of terminally differentiated cells is unknown. To address this question, we designed a conditional gene expression system that allows rapid screening of potential reprogramming factors in mouse retinal glial cells combined with genetic lineage tracing. Using this assay, we found that coexpression of the early temporal identity transcription factors Ikzf1 and Ikzf4 is sufficient to directly convert Müller glial (MG) cells into cells that translocate to the outer nuclear layer (ONL), where photoreceptor cells normally reside. We name these “induced ONL (iONL)” cells. Using genetic lineage tracing, histological, immunohistochemical, and single-cell transcriptome and multiome analyses, we show that expression of Ikzf1/4 in MG in vivo, without retinal injury, mostly generates iONL cells that share molecular characteristics with bipolar cells, although a fraction of them stain for Rxrg, a cone photoreceptor marker. Furthermore, we show that coexpression of Ikzf1 and Ikzf4 can reprogram mouse embryonic fibroblasts to induced neurons in culture by rapidly remodeling chromatin and activating a neuronal gene expression program. This work uncovers general neuronal reprogramming properties for temporal identity factors in terminally differentiated cells."

Gene therapy could help restore vision lost to degenerative disease Scientists in Canada have developed a new technique that may one day help restore some sight to patients with inherited vision impairment. The regenerative therapy works by expressing genes that convert dormant cells into new light-sensing cells in the retina to replace those lost to disease.

New hope for vision regeneration Researchers led by UdeM's Michel Cayouette have found a way to reactivate dormant cells in the retina and transform them to ultimately replace cells lost in retinal degeneration.

Direct neuronal reprogramming by temporal identity factors (open access)

Fig. 1 Ikzf1/4 expression induces morphological reprogramming of MG ex vivo

Trial drug shown to significantly slow early Alzheimer’s decline

Good news! It looks like we are coming closer to an effective treatment!

"A monoclonal antibody, donanemab clears away the plaque by targeting a specific kind of amyloid beta – pyroglutamate-modified amyloid beta.

The trial, known as TRAILBLAZER-ALZ 2, evaluated the safety and efficacy of donanemab on 1,182 people with symptoms of early Alzheimer’s disease, such as mild cognitive impairment. It was compared with lecanemab, another monoclonal antibody drug that targets amyloid beta. While both drugs are given intravenously, donanemab is given every four weeks, whereas lecanemab is given every two. ...

The trial produced some promising results. Assessing the participants’ iADRS scores, the cognitive and functional decline of those who received donanemab was slowed by 35% compared to the placebo group.

At the one-year mark, 47% of participants who took donanemab showed no decline in the CDR-SB, compared to 29% who were given the placebo. And participants on donanemab demonstrated a 39% lower risk of progressing to the next stage of the disease.
The drug significantly reduced brain amyloid plaque levels, as observed using positron emission tomography (PET) brain scans. 34% of participants with intermediate levels of tau protein achieved amyloid clearance at six months; 71% at 12 months. However, despite donanemab clearing amyloid plaques, the disease was not halted completely. ..."

Trial drug shown to significantly slow early Alzheimer’s decline A Phase 3 clinical trial of the drug donanemab has shown it can significantly slow cognitive and functional decline in people with early-stage Alzheimer’s disease, compared with existing treatments.

EXPERT REACTION: Drug reported to slow Alzheimer's progression by 35%

Study Uncovers Biological Mechanism Behind Loss of Smell in Parkinson’s Patients

Good news! Making progress one step at a time!

"About 75-90 percent of Parkinson’s patients report diminishing sense of smell, even prior to the onset of motor symptoms, and is now recognized a non-motor symptom of Parkinson’s disease.

Researchers ... determined the biological mechanisms behind this olfactory impairment by using an alpha-synuclein A30P mouse model used to mimic symptoms of Parkinson’s in mice.

Using buried food tests, the researchers found that the mice with later stage symptoms of Parkinson’s disease exhibited olfactory impairment. They found that those mice with olfactory deficits exhibited severe pathology in projection neurons of the olfactory pathway. They also found these mice showed reduced neurogenesis in the olfactory bulb. In contrast, studies have shown that healthy aging brains continue to form new neurons in the olfactory bulb throughout life. ..."

From the abstract:

"Parkinson's disease (PD) is characterized by multiple symptoms including olfactory dysfunction, whose underlying mechanisms remain unclear. Here, we explored pathologic changes in the olfactory pathway of transgenic (Tg) mice of both sexes expressing the human A30P mutant α-synuclein (α-syn; α-syn-Tg mice) at 6–7 and 12–14 months of age, representing early and late-stages of motor progression, respectively. α-Syn-Tg mice at late stages exhibited olfactory behavioral deficits, which correlated with severe α-syn pathology in projection neurons (PNs) of the olfactory pathway. In parallel, olfactory bulb (OB) neurogenesis in α-syn-Tg mice was reduced in the OB granule cells at six to seven months and OB periglomerular cells at 12–14 months, respectively, both of which could contribute to olfactory dysfunction. Proteomic analyses showed a disruption in endocytic and exocytic pathways in the OB during the early stages which appeared exacerbated at the synaptic terminals when the mice developed olfactory deficits at 12–14 months. Our data suggest that
(1) the α-syn-Tg mice recapitulate the olfactory functional deficits seen in PD;
(2) olfactory structures exhibit spatiotemporal disparities for vulnerability to α-syn pathology;
(3) α-syn pathology is restricted to projection neurons in the olfactory pathway;
(4) neurogenesis in adult α-syn-Tg mice is reduced in the OB; and
(5) synaptic endocytosis and exocytosis defects in the OB may further explain olfactory deficits.

SIGNIFICANCE STATEMENT Olfactory dysfunction is a characteristic symptom of Parkinson's disease (PD). Using the human A30P mutant α-synuclein (α-syn)-expressing mouse model, we demonstrated the appearance of olfactory deficits at late stages of the disease, which was accompanied by the accumulation of α-syn pathology in projection neurons (PNs) of the olfactory system. This dysfunction included a reduction in olfactory bulb (OB) neurogenesis as well as changes in synaptic vesicular transport affecting synaptic function, both of which are likely contributing to olfactory behavioral deficits."

Study Uncovers Biological Mechanism Behind Loss of Smell in Parkinson’s Patients < Neurosurgery

α-Synuclein Pathology and Reduced Neurogenesis in the Olfactory System Affect Olfaction in a Mouse Model of Parkinson's Disease (no public access)

Study reveals a driver of brain cell damage in neurodegeneration

Good news!

"... A new study l... has identified the first known regulator of the complement system in the adult brain: the neuronal pentraxin protein Nptx2. Loss of Nptx2 leaves the cascade unchecked, exacerbating synapse destruction. In models of neurodegeneration, the researchers overcame these effects by boosting Nptx2 levels or blocking complement protein in cells, suggesting that therapeutic strategies targeting the complement system could prevent or even reverse damage to brain cells in neurodegenerative disease. ...
“This study contributes to the emerging picture of the complement cascade’s role across a range of neurological disorders,” ...

The scientists zeroed in on the pentraxin called Nptx2, which is secreted by excitatory neurons and is a biomarker for a range of neurological disorders. In patients with Alzheimer’s disease, frontotemporal dementia, schizophrenia, and Down’s syndrome, Nptx2 is depleted in the cerebrospinal fluid that surrounds the brain and spinal cord.

In their study, the researchers saw that Nptx2 directly and specifically binds and inhibits the activity of C1q, the initiating factor of the complement cascade.

Further, in an animal model lacking Nptx2, they found increased activity of the complement system along with destruction of synapses by microglia. When they eliminated C1q in these animals through genetic deletion or antibody blocking, synapses in the brain tissue recovered.

In an animal model of neurodegeneration marked by overactive microglia and elevated complement activity, boosting the production of Nptx2 in certain brain cells led to a decrease in complement activity and reversed the loss of synapses. ..."

From the abstract:

"Complement overactivation mediates microglial synapse elimination in neurological diseases such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD), but how complement activity is regulated in the brain remains largely unknown. We identified that the secreted neuronal pentraxin Nptx2 binds complement C1q and thereby regulates its activity in the brain. Nptx2-deficient mice show increased complement activity, C1q-dependent microglial synapse engulfment, and loss of excitatory synapses. In a neuroinflammation culture model and in aged TauP301S mice, adeno-associated virus (AAV)–mediated neuronal overexpression of Nptx2 was sufficient to restrain complement activity and ameliorate microglia-mediated synapse loss. Analysis of human cerebrospinal fluid (CSF) samples from a genetic FTD cohort revealed reduced concentrations of Nptx2 and Nptx2-C1q protein complexes in symptomatic patients, which correlated with elevated C1q and activated C3. Together, these results show that Nptx2 regulates complement activity and microglial synapse elimination in the brain and that diminished Nptx2 concentrations might exacerbate complement-mediated neurodegeneration in patients with FTD."

Study reveals a driver of brain cell damage in neurodegeneration | Broad Institute Researchers identify a protein in the brain that regulates the complement cascade, which has been linked to Alzheimer’s disease and schizophrenia and is a possible drug target.

The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration (no public access)

A section of brain from a mouse model of neurodegeneration, showing a control protein in green, Nptx2 in red, and glial cells in white. Boosting Nptx2 rescued synapses and reduced complement overactivity.

Gene therapy approach to boost ‘cold shock protein’ in the brain without cooling protects mice against neurodegenerative disease

Good news! Without cooling! Don't be shocked! 😊

"The discovery is a step towards harnessing the protective effects of cooling the brain to treat patients with acute brain injury and even to prevent dementias, such as Alzheimer’s.

When the body cools down significantly, it increases its levels of RBM3, a molecule known as the cold shock protein – a phenomenon first observed in hibernating animals. It is thought that during hibernation, the protein helps protect the brain from damage and allows it to continue to form new connections. ...

In research ... studied whether a form of gene therapy known as antisense oligonucleotides (ASOs) could increase levels of the cold shock protein in the brains of mice – and hence protect them.

The team examined the gene that codes for production of the cold shock protein and found that it contains a key element which under normal conditions prevents its expression.  Removing, or ‘dialling down’ this element using an ASO, results in a long-lasting boost to production of RBM3. ..."

From the abstract:

"Neurodegenerative diseases are increasingly prevalent in the aging population, yet no disease-modifying treatments are currently available. Increasing the expression of the cold-shock protein RBM3 through therapeutic hypothermia is remarkably neuroprotective. However, systemic cooling poses a health risk, strongly limiting its clinical application. Selective upregulation of RBM3 at normothermia thus holds immense therapeutic potential. Here we identify a poison exon within the RBM3 gene that is solely responsible for its cold-induced expression. Genetic removal or antisense oligonucleotide (ASO)-mediated manipulation of this exon yields high RBM3 levels independent of cooling. Notably, a single administration of ASO to exclude the poison exon, using FDA-approved chemistry, results in long-lasting increased RBM3 expression in mouse brains. In prion-diseased mice, this treatment leads to remarkable neuroprotection, with prevention of neuronal loss and spongiosis despite high levels of disease-associated prion protein. Our promising results in mice support the possibility that RBM3-inducing ASOs might also deliver neuroprotection in humans in conditions ranging from acute brain injury to Alzheimer's disease."

Gene therapy approach to boost ‘cold shock protein’ in the brain without cooling protects mice against neurodegenerative disease | University of Cambridge Scientists in Cambridge and Berlin have used a form of gene therapy to increase levels of the so-called ‘cold shock protein’ in the brains of mice, protecting them against the potentially devastating impact of prion disease.

ASO targeting RBM3 temperature-controlled poison exon splicing prevents neurodegeneration in vivo (open access)

Synopsis

Figure 1.

RBM3 intron 3 contains an evolutionary conserved heat-induced poison exon

Big study uncovers 22 links between viral infections and neurodegenerative diseases

Good news! Get your annual flu shot!

"New research looking at health records from nearly half a million people has identified 22 different associations between viral infections and neurodegenerative diseases. Influenza, encephalitis and other viral infections all were linked to increased rates of brain diseases such as Parkinson's, Alzheimer's and MS. ...
Back in the 1950s microbial infections were suggested to be the source of many neurodegenerative diseases ... Although the idea sat on the fringes of neuroscience for decades ... a handful of key studies uncovered strong, novel evidence. In particular, a study published early in 2022 presented robust causal evidence linking the development of multiple sclerosis (MS) to infection with the Epstein-Barr virus (EBV). ...
do raise the possibility that broader deployment of common vaccines could potentially reduce rates of neurodegenerative disease. If neurodegenerative disease is primarily accelerated by severe viral infections then vaccinations known to reduce the severity of illness could slow things down for many people. This effect has been somewhat detected in studies linking a reduced risk of Alzheimer's disease in elderly subjects receiving annual flu vaccinations. ..."

"... “Keep in mind that the individuals we studied did not have the common cold. Their infections made them so sick that they had to go to the hospital,” ..."

From the highlights and abstract:

"Highlights

• Identified 45 pairs of viral exposures associated with increased risk of NDDs

• Replicated 22 of the viral exposures/NDD pairings

• Replicated the previously reported Epstein-Barr and multiple sclerosis association

• Follow-up shows significantly elevated risk of NDD years after viral exposure

Summary

With recent findings connecting the Epstein-Barr virus to an increased risk of multiple sclerosis and growing concerns regarding the neurological impact of the coronavirus pandemic, we examined potential links between viral exposures and neurodegenerative disease risk. Using time series data from FinnGen for discovery and cross-sectional data from the UK Biobank for replication, we identified 45 viral exposures significantly associated with increased risk of neurodegenerative disease and replicated 22 of these associations. The largest effect association was between viral encephalitis exposure and Alzheimer’s disease. Influenza with pneumonia was significantly associated with five of the six neurodegenerative diseases studied. We also replicated the Epstein-Barr/multiple sclerosis association. Some of these exposures were associated with an increased risk of neurodegeneration up to 15 years after infection. As vaccines are currently available for some of the associated viruses, vaccination may be a way to reduce some risk of neurodegenerative disease."

Big study uncovers 22 links between viral infections and brain disease

Could a viral illness increase chances of developing Alzheimer’s or other neurodegenerative disease?

Virus exposure and neurodegenerative disease risk across national biobanks (open access)

New evidence links nasal viral infections to rapid Alzheimer's progression

Figure 1: Graphical summary of hazard ratio lag for replicated viral/NDD pairs

How Huntington’s disease affects two distinct cell populations in the striatum

Good news!

"In patients with Huntington’s disease, neurons in a part of the brain called the striatum are among the hardest-hit. Degeneration of these neurons contributes to patients’ loss of motor control, which is one of the major hallmarks of the disease.

Neuroscientists ... have now shown that two distinct cell populations in the striatum are affected differently by Huntington’s disease. They believe that neurodegeneration of one of these populations leads to motor impairments, while damage to the other population, located in structures called striosomes, may account for the mood disorders that are often seen in the early stages of the disease.

“As many as 10 years ahead of the motor diagnosis, Huntington’s patients can experience mood disorders, and one possibility is that the striosomes might be involved in these,” ...
Using single-cell RNA sequencing to analyze the genes expressed in mouse models of Huntington’s disease and postmortem brain samples from Huntington’s patients, the researchers found that cells of the striosomes and another structure, the matrix, begin to lose their distinguishing features as the disease progresses.  ...
This kind of analysis could also shed light on other brain disorders that affect the striatum, such as Parkinson’s disease and autism spectrum disorder, the researchers say. ...
The researchers also found that these four major cell types begin to lose their identifying molecular identities and become more difficult to distinguish from one another in Huntington’s disease. “Overall, the distinction between striosomes and matrix becomes really blurry,” ...
Previous research has shown that overactivity of striosomes can lead to the development of repetitive behaviors such as those seen in autism, obsessive compulsive disorder, and Tourette’s syndrome. ..."

From the abstract:

"Striatal projection neurons (SPNs), which progressively degenerate in human patients with Huntington’s disease (HD), are classified along two axes: the canonical direct-indirect pathway division and the striosome-matrix compartmentation. It is well established that the indirect-pathway SPNs are susceptible to neurodegeneration and transcriptomic disturbances, but less is known about how the striosome-matrix axis is compromised in HD in relation to the canonical axis. Here we show, using single-nucleus RNA-sequencing data from male Grade 1 HD patient post-mortem brain samples and male zQ175 and R6/2 mouse models, that the two axes are multiplexed and differentially compromised in HD. In human HD, striosomal indirect-pathway SPNs are the most depleted SPN population. In mouse HD models, the transcriptomic distinctiveness of striosome-matrix SPNs is diminished more than that of direct-indirect pathway SPNs. Furthermore, the loss of striosome-matrix distinction is more prominent within indirect-pathway SPNs. These results open the possibility that the canonical direct-indirect pathway and striosome-matrix compartments are differentially compromised in late and early stages of disease progression, respectively, differentially contributing to the symptoms, thus calling for distinct therapeutic strategies."

How Huntington’s disease affects different neurons | MIT News | Massachusetts Institute of Technology A new study identifies cells that are the most vulnerable within a brain structure involved in mood and movement.

Transcriptional vulnerabilities of striatal neurons in human and rodent models of Huntington’s disease (open access)

Fig. 1: Identification and characterization of human and rodent SPN cell-type-specific markers