Cannabidiol (CBD) further confirmed to reverse brain damage in mouse model of Alzheimer's disease

Good news!

"... The non-psychoactive compound derived from the Cannabis sativa plant, called cannabidiol (CBD), was recently found to show promise for protecting brain cells from damage.

Compared to Δ9-tetrahydrocannabinol (THC), the compound in cannabis that elicits feelings of euphoria and alters a user's mental state, CBD is safer and could thus be easier to introduce in clinical settings. ...

Du and her colleagues studied a mouse model of AD known as triple-transgenic AD mice. These are genetically modified mice whose synapses become progressively damaged, following the formation of Tau protein tangles and the accumulation of Aβ. These mice exhibit characteristics that resemble those observed in patients with AD, such as memory loss and anxiety-like behaviors.

First, the researchers treated the mice with CBD six days per week for a total period of 45 days. After this treatment period, they observed the mice's behavior and examined their brains.

Interestingly, they found that the mice's memory had improved after treatment and their anxiety levels appeared lower. In addition, dendritic spines in their brains and the overall structure of synapses (i.e., junctions between neurons) appeared to be restored.

"We next looked at how CBD achieves the effects we observed," said Du. "We found that it activates the TrkB-PI3K-AKT pathway—a critical pathway for neuronal survival and plasticity. ..."

From the abstract:

"Alzheimer’s disease (AD) is characterized by progressive synaptic failure, neuroinflammation, amyloid and tau pathology, yet effective disease-modifying therapies remain limited. Cannabidiol (CBD) has shown neuroprotective potential in AD, but its direct molecular targets and signaling mechanisms remain unclear. Here, we demonstrate that CBD ameliorates cognitive and emotional deficits in 3×Tg-AD mice by restoring synaptic integrity and plasticity.

At the mechanistic level, CBD activated TrkB signaling independently of BDNF, leading to suppression of tau hyperphosphorylation via the PI3K/AKT/GSK3β pathway and attenuation of neuroinflammation and amyloid pathology through inhibition of the JAK2/STAT3/SOCS1 axis.

Using isothermal shift assays combined with biophysical binding analyses, we identified FRS2, a core adaptor protein of TrkB, as a direct molecular target of CBD. 

Molecular dynamics simulations further revealed that CBD stabilizes the FRS2–TrkB interface, thereby facilitating TrkB activation.

Importantly, genetic knockdown of FRS2 abolished CBD-induced TrkB signaling and its downstream neuroprotective effects in both cellular and in vivo AD models. Together, these findings identify FRS2 as a critical signaling node mediating BDNF-independent TrkB activation by CBD and establish a mechanistic framework linking CBD to disease-modifying pathways in AD."

CBD found to reverse brain damage in mouse model of Alzheimer's disease

Mechanistic insights into cannabidiol-mediated TrkB activation via FRS2 interaction in attenuating Alzheimer’s disease pathology and cognitive impairment

New drug NU-9 shows promise against early Alzheimer's in a mouse model

Good news! New drug development is too slow as this case exemplifies again! Hopefully, in the near future machine learning & AI will accelerate drug development!

"... That’s why a new study from Northwestern University offers so much hope, because if researchers there are correct, their new small-molecule NU-9 drug may be able to stop Alzheimer’s disease long before it begins ruining lives. ..."

"... An experimental drug developed at Northwestern University has demonstrated further promise as an early intervention for Alzheimer’s disease.

In a new study, Northwestern scientists identified a previously unknown highly toxic sub-species of amyloid beta oligomers — toxic clusters of peptides — that appear to drive several of the brain’s earliest changes, including neuronal dysfunction, inflammation and activation of immune cells.

The experimental drug, a small-molecule compound called NU-9, decreased this toxic amyloid beta oligomer subtype and dramatically reduced the damage it causes in a mouse model of Alzheimer’s disease. ..."

"... Conceived about 15 years ago, NU-9 emerged as part of Silverman’s multi-year effort to discover a small molecule compound that could prevent toxic protein aggregate buildup in neurodegenerative diseases. By 2021, NU-9 demonstrated efficacy in animal models of amyotrophic lateral sclerosis (ALS), clearing toxic SOD1 and TDP-43 proteins and restoring health to upper motor neurons. In 2024, it received clearance from the U.S. Food and Drug Administration to begin human clinical trials for ALS. ..."

From the abstract:

"INTRODUCTION

Neuronal degeneration and immune cell activation occur early in Alzheimer's disease (AD), but the responsible molecules remain undetermined. While exogenous amyloid beta oligomers (AβOs) induce neuronal death and gliosis, the role of endogenous AβOs is less defined.

METHODS

Brain sections from 1- to 12-month-old 5xFAD mice were immunolabeled for AβOs, activated glia, phosphorylated transactive response DNA-binding protein 43 kDa (pTDP-43), and other AD markers. Neuropathology was analyzed following 60-day oral treatment with NU-9, a small-molecule AβO inhibitor.

RESULTS

By 8 weeks, AβOs accumulated in the subiculum alongside early reactive astrocytes and activated microglia.

Clinical-stage antibody ACU193 detected AβOs in early-stage degenerating neurons, while NU4-labeled denser deposits in late-stage degenerating neurons. ACU193+ AβOs accumulated on reactive astrocyte surfaces, which also contained pTDP-43, and later emerged inside activated microglia.

NU-9 reduced astrocyte-associated ACU193+ AβOs, pTDP-43, and markedly diminished glial fibrillary acidic protein.

DISCUSSION

These findings demonstrate in vivo efficacy of NU-9 and support targeting ACU193+ AβOs to mitigate AD progression.

Highlights

• ACU193+ AβOs accumulated as puncta in neurons at an early stage of degeneration, while NU4+ AβOs appeared as dense deposits only in late-stage degenerating neurons.
• The onset and progression of ACU193+ AβOs paralleled activated microglia and reactive astrocytes.
• ACU193+ AβOs significantly increased on reactive astrocyte surfaces, as NU4+ AβOs accumulated in halos around Thio-S+ plaque cores.
• In older mice, the ACU193 signal decreased on astrocytes and was found inside activated microglia.
• Sixty-day oral NU-9 treatment significantly reduced astrocyte ACU193+ AβOs and markedly decreased reactive astrogliosis.

..."

New drug NU-9 shows promise against early Alzheimer's

NU-9 halts Alzheimer’s disease in animal model before symptoms begin (original news release) "Study uncovers a new Alzheimer’s trigger — and a way to stop it"

Identification of a glia-associated amyloid β oligomer subtype and the rescue from reactive astrogliosis by inhibitor NU-9 (open access)

Fig. 8 Oral treatment with NU-9 reduces astrocyte-associated ACU193+ amyloid beta oligomers and pTDP-43+ ubiquitinated aggregates, and rescues GFAP levels.

Diabetes drug and antihistamine could together repair multiple sclerosis damage, trial finds

Good news! It appears, the results of this study are not yet published in a journal.

"A combination of metformin, a common diabetes drug, and clemastine, an antihistamine, can help repair myelin – the protective coating around nerves, which gets damaged in multiple sclerosis (MS) causing symptoms like fatigue, pain, spasms and problems with walking. ...

Some 70 people with relapsing MS took part in the trials for six months, half of whom took the drug combination and half took a placebo. The primary outcome used to gauge the effectiveness of the drug was a ‘visual evoked potential’ test, which measures how quickly signals travel between the eyes and the brain. The speed of signals slowed down in the placebo group over the course of six months, but remained constant in the drug group. ..."

Diabetes drug and antihistamine could together repair multiple sclerosis damage, trial finds | University of Cambridge "Scientists behind the trial say they are “on the brink of a new class of treatments” and that the findings take us another step closer to stopping disease progression in MS."

Accelerating global Alzheimer’s Research

Good news!

"Key insights in Alzheimer’s research are being fueled by a “massive” new trove of globally shared data—with breakthroughs showing the power and potential of multinational collaboration, per a new series published in Nature. 

Background: The Global Neurodegeneration Proteomics Consortium (GNPC), launched in 2023, is now the largest neurodegenerative disease data-sharing effort, including 40,000+ clinical samples and 250 million protein measurements that allow for “unprecedented” research—potentially speeding up the development of diagnostics and therapies by decades.

Discoveries include: 

• New insights about APOE4, a gene variant that most strongly increases risk for developing Alzheimer’s, and new proteins associated with the gene. 
• New evidence linking different neurodegenerative diseases with aging in other organs, including the liver, intestines, and muscles.
• Identification of protein pathways shared across several neurodegenerative diseases.

...

Other breakthroughs: Meanwhile, new research shows that Alzheimer’s-related biomarkers can be detected in the blood of adults as young as 41, per a Finnish study published in The Lancet’s Healthy Longevity—suggesting the disease could be identified decades before symptoms appear ..."

Global Health NOW: Accelerating Alzheimer’s Research; Replacing Aid With ‘Sin Taxes’; and Molar Express

Global Neurodegeneration Proteomics Consortium (GNPC)

GNPC

Two new potential Alzheimer's cures discovered back to back

Amazing stuff!

"Researchers have discovered that newborns have high levels of the tau protein, which is elevated in older people with Alzheimer’s disease, but that it causes them no harm. The discovery opens the door to developing new ways of treating or preventing the neurodegenerative condition. ...

Now, a new international study led by researchers ... has made a stunning finding: the elevated levels of tau seen in patients with Alzheimer’s disease are also seen in newborns. The discovery could provide a roadmap for developing new treatments for the degenerative condition. ..."

"What do the brains of newborns and patients with Alzheimer's disease have in common? Researchers ... recently reported that both newborns and Alzheimer's patients have elevated blood levels of a protein called phosphorylated tau, specifically a form called p-tau217. ..."

From the abstract (1):

"Tau phosphorylation plays an important role in brain physiology and pathology. During foetal development, it supports microtubule dynamics and neuroplasticity, whereas in Alzheimer’s disease (AD), it drives pathological tau aggregation and tangle formation.

In this multicentre study (n = 462), we measured plasma phosphorylated-tau217 in healthy newborns, premature infants, patients with AD and healthy controls across various age groups.

Plasma phosphorylated-tau217 levels were significantly higher in newborns compared to healthy individuals of any age group and even exceeded levels observed in patients with AD.

In newborns, plasma phosphorylated-tau217 levels inversely correlated with perinatal factors such as gestational age.

Longitudinal analysis of preterm infants demonstrated a decline in serum phosphorylated-tau217 levels over the first months of life, approaching levels observed in young adults.

In contrast, elevated plasma phosphorylated-tau217 in older individuals was associated with AD pathology.

Our findings corroborate the crucial role of tau phosphorylation in early brain development. However, in AD, tau phosphorylation transitions into a pathological mechanism.

The high levels of blood-based phosphorylated-tau217 observed at birth and subsequent clearance might indicate distinct regulatory mechanisms that prevent tau aggregation in early life. Further studies are needed to explore the shared mechanisms of tau phosphorylation in newborns and AD."

"Remarkable new findings about the sugar stores in neurons have unlocked an entire new method of treating Alzheimer's disease and other cognitive decline, and it goes a long way to explaining why there's a growing body of evidence linking GLP-1 weight loss drugs to protection from dementia. ...

Scientists ... made this discovery when investigating the often overlooked glycogen stores in our neurons, which has largely been viewed as a redundant aspect of our biology until now. The researchers found that the metabolism of this sugar – a stored form of glucose – appears to protect the brain from toxic tau build-up and cognitive decline. ..."

"... Glycogen is typically thought of as a reserve energy source stored in the liver and muscles. While small amounts also exist in the brain, particularly in support cells called astrocytes, its role in neurons has long been dismissed as negligible. ...

The research team ... discovered that in both fly and human models of tauopathy (a group of neurodegenerative diseases including Alzheimer’s), neurons accumulate excessive glycogen. More importantly, this buildup appears to contribute to disease progression. ... tau ... appears to physically bind to glycogen, trapping it and preventing its breakdown. ...

When glycogen can’t be broken down, the neurons lose an essential mechanism for managing oxidative stress, a key feature in aging and neurodegeneration. By restoring the activity of an enzyme called glycogen phosphorylase (GlyP)—which kicks off the process of glycogen breakdown—the researchers found they could reduce tau-related damage in fruit flies and human stem cell-derived neurons. ...

Rather than using glycogen as a fuel for energy production, these enzyme-supported neurons rerouted the sugar molecules into the pentose phosphate pathway (PPP)—a critical route for generating NADPH (nicotinamide adenine dinucleotide phosphate) and Glutathione, molecules that protect against oxidative stress. “By increasing GlyP activity, the brain cells could better detoxify harmful reactive oxygen species, thereby reducing damage and even extending the lifespan of tauopathy model flies,”  ...

Even more promising, the team demonstrated that dietary restriction (DR)—a well-known intervention to extend lifespan—naturally enhanced GlyP activity and improved tau-related outcomes in flies. They further mimicked these effects pharmacologically using a molecule called 8-Br-cAMP, showing that the benefits of DR might be reproduced through drug-based activation of this sugar-clearing system. “This work could explain why GLP-1 drugs, now widely used for weight loss, show promise against dementia, potentially by mimicking dietary restriction ..."

From the abstract (2):

"Tauopathies encompass a range of neurodegenerative disorders, such as Alzheimer’s disease (AD) and frontotemporal lobar degeneration with tau inclusions (FTLD-tau), for which there are currently no successful treatments. Here, we show impaired glycogen metabolism in the brain of a tauopathy Drosophila melanogaster model and people with AD, indicating a link between tauopathies and glycogen metabolism.

We demonstrate that the breakdown of neuronal glycogen ameliorates the tauopathy phenotypes in flies and induced pluripotent stem cell (iPSC)-derived neurons from people with FTLD-tau.

Glycogen breakdown redirects glucose flux to the pentose phosphate pathway and alleviates oxidative stress.

Our findings uncover a critical role for the neuroprotective effects of dietary restriction (DR) by increasing glycogen breakdown. Mechanistically, we show a potential interaction between tau protein and glycogen, suggesting a vicious cycle in which tau binding promotes glycogen accumulation in neurons, which in turn exacerbates tau accumulation which further disrupts cellular homeostasis. Our studies identify impaired glycogen metabolism as a key hallmark for tauopathies and offer a promising therapeutic target in tauopathy and other neurodegenerative diseases."

Newborns' tau protein levels may unlock Alzheimer's cure

Newborns have elevated levels of a biomarker for Alzheimer's (original news release) "Newborn babies and patients with Alzheimer's disease share an unexpected biological trait: elevated levels of a well-known biomarker for Alzheimer's. This is shown in a study led by researchers at the University of Gothenburg."

The potential dual role of tau phosphorylation: plasma phosphorylated-tau217 in newborns and Alzheimer’s disease (1, open access)

Breakthrough brain sugar discovery turns the tables on Alzheimer's disease

Neurons burn sugar differently. The discovery could save the brain. (original news release) "In addition to a new approach in Alzheimer’s research, study from Buck Institute could explain why GLP-1 drugs show promise against dementia"

Neuronal glycogen breakdown mitigates tauopathy via pentose-phosphate-pathway-mediated oxidative stress reduction (2, no public access)

Graphical abstract (1)

The image shows brain cells (neurons) where two substances are highlighted: tau, appears in red, and glycogen appears in green. Where the two overlap, the color turns yellow or orange, showing they are located close together. Follow-up experiments confirmed that in Alzheimer’s disease, glycogen builds up in brain cells and can stick to tau. This discovery suggests that glycogen may play a role in helping tau clump together—a harmful process believed to drive Alzheimer’s and similar brain disorders.

How sensory gamma rhythm stimulation clears amyloid in Alzheimer’s mice

Good news!

"Studies at MIT and elsewhere are producing mounting evidence that light flickering and sound clicking at the gamma brain rhythm frequency of 40 hertz (Hz) can reduce Alzheimer’s disease (AD) progression and treat symptoms in human volunteers as well as lab mice. In a new open-access study in Nature using a mouse model of the disease, MIT researchers reveal a key mechanism that may contribute to these beneficial effects: clearance of amyloid proteins, a hallmark of AD pathology, via the brain’s glymphatic system, a recently discovered “plumbing” network parallel to the brain’s blood vessels. ..."

From the abstract:

"The glymphatic movement of fluid through the brain removes metabolic waste. Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer’s disease. Here we show that multisensory gamma stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer’s disease. Influx of cerebrospinal fluid was associated with increased aquaporin-4 polarization along astrocytic endfeet and dilated meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signalling, we found that vasoactive intestinal peptide interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings establish novel mechanisms that recruit the glymphatic system to remove brain amyloid."

How sensory gamma rhythm stimulation clears amyloid in Alzheimer’s mice | MIT News | Massachusetts Institute of Technology Study finds stimulating a key brain rhythm with light and sound increases peptide release from interneurons, driving clearance of an Alzheimer’s protein.

Multisensory gamma stimulation promotes glymphatic clearance of amyloid (open access)

Fig. 1: Multisensory 40 Hz stimulation promotes AQP4-dependent clearance of amyloid.

Multisensory gamma stimulation promotes glymphatic clearance of amyloid (open access)

Hallmarks of dementia found well before diagnosis in one large family living in Colombia

Good news! Will we soon have regular checkups? 

However, this is a very specialized study focusing only on one large family living in one city located in Colombia. 

"A new study led by investigators at Massachusetts General Hospital shows that early accumulation of amyloid-β and tau protein begins to disrupt the brain’s connections important for memory years before signs of cognitive impairment were observed. ...

To learn more about this phenomenon, [researchers] used positron emission tomography (PET) for tau and amyloid-β, and functional magnetic resonance imaging (fMRI) to study how Alzheimer’s disease pathologies related to connectivity of brain regions and networks in individuals from a large family of more than 6,000 living members with Alzheimer’s disease prevalence from Antioquia, Colombia, South America.

Those who have the mutation known as Presenilin-1 E280A) are almost certain to develop Alzheimer’s disease dementia, usually showing signs of mild cognitive impairment (MCI) at age 44 and dementia by the age of 49. None of the individuals studied had any cognitive symptoms yet. ...
Previously, this research team showed that these individuals exhibit high levels of amyloid-β almost two decades before the onset of MCI, and tau pathology close to six years before onset. ...
The team used fMRI to examine regions of the brain at the voxel level, akin to pixels that represent 3D units encompassing millions of brain cells, to look at connectivity within and between different networks of the brain. They learned that mutation carriers displayed connection disruptions in the brain’s main memory network years before onset of cognitive impairment in the family. The researchers also developed a novel mathematical approach merging both fMRI and molecular imaging to see more clearly when brain regions begin to disconnect during the disease process. ..."

From the abstract:

"... We used high-resolution (voxel-level) graph-based network analyses to test whether in vivo amyloid-β and tau burden was associated with the segregation and integration of brain functional connections, and episodic memory, in cognitively unimpaired Presenilin-1 E280A carriers who are expected to develop early-onset AD dementia in ∼13 y on average. Compared to noncarriers, mutation carriers exhibited less functional segregation and integration in posterior default-mode network (DMN) regions, particularly the precuneus, and in the retrospenial cortex, which has been shown to link medial temporal regions and cortical regions of the DMN. Mutation carriers also showed greater functional segregation and integration in regions connected to the salience network, including the striatum and thalamus. Greater tau burden was associated with lower segregated and integrated functional connectivity of DMN regions, particularly the precuneus and medial prefrontal cortex. In turn, greater tau pathology was related to higher segregated and integrated functional connectivity in the retrospenial cortex and the anterior cingulate cortex, a hub of the salience network. These findings enlighten our understanding of how AD-related pathology distinctly alters the brain’s functional architecture in the preclinical stage, possibly contributing to pathology propagation and ultimately resulting in dementia."

Hallmarks of dementia found well before diagnosis – Harvard Gazette Accumulation of amyloid-β and tau proteins are related to brain network changes years before symptoms

Amyloid-β and tau pathologies relate to distinctive brain dysconnectomics in preclinical autosomal-dominant Alzheimer’s disease (no public access)

Mutations in Noncoding DNA Protect the Brain from ALS

Good news!

"... Mutations in over 25 genes, for example, are associated with amyotrophic lateral sclerosis, or ALS, and they all increase the risk of developing this incurable disorder. Now, a research team ... has linked a new gene to ALS, but this one contains mutations of a different sort: They seem to play a defensive, rather than an offensive, role in the disease. ...
The Weizmann scientists focused on a gene called IL18RAP, long known to affect microglia, and found that it can contain mutations that mitigate the microglia’s toxic effects. “We have identified mutations in this gene that reduce inflammation,” ...
It is therefore extremely rare for ALS patients to have these protective mutations, and those rare patients who do harbor them tend to develop the disease roughly six years later, on average, than those without the mutations. In other words, the mutations seem to be linked to a core ALS process, slowing the disease down. ...
To confirm the findings, the researchers used gene-editing technology to introduce the protective mutations into stem cells from patients with ALS, causing these cells to mature into microglia in a laboratory dish. They then cultured microglia, with or without the protective mutations, in the same dishes with motor neurons. Microglia harboring the protective mutations were found to be less aggressive toward motor neurons than microglia that did not have the mutations. “Motor neurons survived significantly longer when cultured with protective microglia, rather than with regular ones,”"

From the abstract:

"... Here, we performed region-based rare variant association analysis of >25,000 variants in untranslated regions of 6,139 amyotrophic lateral sclerosis (ALS) whole genomes and the whole genomes of 70,403 non-ALS controls. We identified interleukin-18 receptor accessory protein (IL18RAP) 3′ untranslated region (3′UTR) variants as significantly enriched in non-ALS genomes and associated with a fivefold reduced risk of developing ALS, and this was replicated in an independent cohort. These variants in the IL18RAP 3′UTR reduce mRNA stability and the binding of double-stranded RNA (dsRNA)-binding proteins. Finally, the variants of the IL18RAP 3′UTR confer a survival advantage for motor neurons because they dampen neurotoxicity of human induced pluripotent stem cell (iPSC)-derived microglia bearing an ALS-associated expansion in C9orf72, and this depends on NF-κB signaling. This study reveals genetic variants that protect against ALS by reducing neuroinflammation and emphasizes the importance of noncoding genetic association studies."

Mutations in Noncoding DNA Protect the Brain from ALS - Life Sciences | Weizmann Wonder Wander - News, Features and Discoveries Weizmann Institute of Science researchers discover a new neuroprotective pathway

Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3′UTR protect against ALS (no public access)

Familial natural short sleep mutations reduce Alzheimer pathology in mice

"Elite sleep genes allow lucky few to get full night's sleep in just 4 hours" I could use some of these genes! :-) 

The age of human genome editing to improve our health etc. is coming! Nature had billions of years, humans can do it faster and better.

In a previous blog post, I recommended to remove the annoying sneezing gene forever!

"... People who are able to function fully on four to six hours of sleep have what scientists call Familial Natural Short Sleep (FNSS). [researcher] has been studying people with FNSS for over a decade. Previous studies showed that FNSS runs in the family. Five genes have been identified thus far linked to FNSS. ...
research also suggests that people with FNSS, which he calls ‘elite sleepers’, have above-average psychological resilience and resistance to neurodegenerative diseases like Alzheimer’s. ..."

From the abstract:

"Although numerous studies have demonstrated that poor sleep increases the development of AD, direct evidence elucidating the benefits of good sleep on the AD pathogenesis is lacking. Familial Natural Short Sleepers (FNSS) are genetically wired to have lifelong reduction in nightly sleep duration without evident consequence on cognitive demise, implying that they may have better sleep quality. Here we investigated two FNSS mutations, DEC2-P384R and Npsr1-Y206H, on the development of tau and amyloid pathology in AD-like mouse models. We found that the development of tau pathology is attenuated in the hippocampus of tau mice carrying FNSS mutations. We also found that DEC2-P384R;5XFAD and female Npsr1-Y206H;5XFAD mice exhibit significantly less amyloid plaques than control mice at 6 months of age. Together, these results reveal that these two FNSS alleles are strong genetic modifiers of AD pathology and may confer resilience to the progression of tau pathology and amyloid plaque formation in neurodegeneration."

Elite sleep genes allow lucky few to get full night's sleep in just 4 hours These genes could be targeted by drugs that improve the quality of sleep for all.

Familial natural short sleep mutations reduce Alzheimer pathology in mice

Exercise improves Alzheimer’s Disease via hormone irisin

Good news! Exercise more! This might be a long awaited breakthrough!

"New insight into the workings of the hormone irisin shows it has the ability to spur the cognitive benefits of exercise, holding promise for treating cognitive decline in Alzheimer's disease, Harvard Medical School scientists at Massachusetts General Hospital have found.

In a study published in Nature Metabolism, the research team report that irisin, secreted by muscles during exercise, could be an effective therapeutic for addressing deficits of the brain that result from Alzheimer’s disease. ...
“For the first time, we showed that soluble irisin, and not its full-length parent protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function,” ...
irisin, a small natural peptide, would be much easier to develop into a therapeutic than the much larger membrane-bound protein FNDC5
discovered irisin was able to cross the blood-brain barrier and directly affect the brain. ...
discovered irisin in 2012 ...
Researchers were further encouraged by the fact that irisin treatment was effective in Alzheimer’s disease mouse models even after the development of significant pathology. ...
Another important finding of the study is that irisin protects against neuroinflammation by acting directly on glial cells in the brain. ...
“Since irisin does not specifically target amyloid plaques, but rather neuroinflammation directly, we’re optimistic it could have beneficial effects on neurodegenerative diseases beyond just Alzheimer’s,” ..."

"Identifying secreted mediators that drive the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in ageing or Alzheimer’s disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function. ...
Diminished pattern separation in F5KO mice can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. ...
Importantly, elevation of circulating irisin levels by peripheral delivery of irisin via adeno-associated viral overexpression in the liver results in enrichment of central irisin and is sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of the cognitive benefits of exercise and is a potential therapeutic agent for treating cognitive disorders including AD."

Exercise and Alzheimer’s Disease | Harvard Medical School Hormone found to confer benefits of exercise on cognitive function

Exercise hormone irisin is a critical regulator of cognitive function (no public access)

Study offers an explanation for why the APOE4 gene enhances Alzheimer’s risk

Good news!

"APOE4 is a strong genetic risk factor for many diseases, most notably, late-onset Alzheimer’s disease. Sienski et al. now show that cultured human glia with an APOE4 genotype accumulated unsaturated triglycerides leading to a lipid imbalance. Using genetic screens in yeast, the authors discovered that promoting phospholipid synthesis through choline supplementation of culture medium restored a normal lipid state in APOE4-expressing yeast cells. The authors then demonstrated that choline supplementation also restored lipid homeostasis in human APOE4 astrocytes. These findings suggest that modulating glial metabolism could help to reduce APOE4-associated disease risk."

"The E4 allele of the apolipoprotein E gene (APOE) has been established as a genetic risk factor for many diseases including cardiovascular diseases and Alzheimer’s disease (AD), yet its mechanism of action remains poorly understood. APOE is a lipid transport protein, and the dysregulation of lipids has recently emerged as a key feature of several neurodegenerative diseases including AD. ..."

"One of the most significant genetic risk factors for developing Alzheimer’s disease is a gene called APOE4, which is carried by almost half of all Alzheimer’s patients. A new study from MIT shows that this gene has widespread effects on brain cells’ ability to metabolize lipids and respond to stress. ...
The researchers hope that their findings will lead to clinical studies of choline in people who carry the APOE4 gene, who make up about 14 percent of the overall population. ...
The human gene for APOE, or apolipoprotein E, comes in three versions. While APOE4 is linked to higher risk for Alzheimer’s, APOE2 is considered protective, and APOE3, the most common variant, is neutral. ...
APOE4 astrocytes showed dramatic changes in how they process lipids compared to APOE3. In APOE4 astrocytes, there was a significant buildup of neutral lipids and cholesterol. These astrocytes also accumulated droplets containing a type of lipids called triglycerides, and these triglycerides had many more unsaturated fatty acid chains than normal. These changes all disrupt the normal lipid balance inside the cells. The authors also noted APOE4-dependent lipid disruptions in another important brain cell, microglia. ...
Choline is naturally found in foods such as eggs, meat, fish, and some beans and nuts. The minimum recommended intake of choline is 550 milligrams per day for men and 425 milligrams per day for women, but most people don’t consume that much, Tsai says. The new study offers preliminary evidence that people who carry the APOE4 gene may benefit from taking choline supplements, she says, although clinical trials are necessary to confirm that. ..."

Study offers an explanation for why the APOE4 gene enhances Alzheimer’s risk | MIT News | Massachusetts Institute of Technology The gene variant disrupts lipid metabolism, but in cell experiments the effects were reversed by choline supplements.

Here is the referenced paper:

APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia (behind paywall)

A Tweak to Immune Cells Reverses Aging in Mice

Good news! Towards a cure for Alzheimer's disease in the next 5-15 years! Research is turning from many years of painstaking analysis to targeted intervention!

"... that deleting the EP2 receptor in mouse macrophages and brain-specific microglia ... reduces inflammation and increases neuronal survival in response to both a bacterial toxin and a neurotoxin. ...
The cells from older [blood] donors made much more PGE2 and had higher abundance of the EP2 receptor than did macrophages from younger donors. When the researchers exposed human macrophages to PGE2, the cells altered their metabolism. Rather than using glucose to make energy, the cells converted it to glycogen and stored it, locking it up where the mitochondria couldn’t access it for ATP production. ..."

"Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty ... Systemically, circulating pro-inflammatory factors can promote cognitive decline, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration ...
In ageing macrophages and microglia, PGE2 signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. ..."

A Tweak to Immune Cells Reverses Aging in Mice | The Scientist Magazine® Knocking out the receptor for a lipid that causes inflammation rejuvenates macrophage metabolism and restores cognitive function in an Alzheimer’s disease model.

Here is the link to the underlying research paper:

Restoring metabolism of myeloid cells reverses cognitive decline in ageing (open access)

There is even a very long commentary published by Nature on this paper:

Reversal of immune-cell shutdown protects the ageing brain Immune cells called macrophages have been found to shut down major metabolic pathways during ageing. Restoring metabolism in these cells is sufficient to alleviate age-associated cognitive decline in mice.

New Tracer Gives Clear Picture of Alzheimer's and Other Dementias

Good news!

"The tracing agent, which highlights the accumulation of toxic tau protein deposits in the brain, could distinguish between a range of conditions called tauopathies that can be difficult to tell apart at the early stages, such as frontotemporal dementia and progressive supranuclear palsy. ...

The new tracer, known as 18F-PM-PBB3, carries a radioactive fluorine isotope to the tau tangles and releases a positron particle detected by a PET scanner when it binds its target. ... their tracer also had the unexpected effect of binding to a greater variety of tau deposits seen across different tauopathies. This means that the same tracer could be used as a diagnostic test for multiple neurodegenerative conditions."

New Tracer Gives Clear Picture of Alzheimer's and Other Dementias | The Scientist Magazine® An imaging agent reveals aggregated tau protein in the brain during PET scans and could improve the diagnosis of neurodegenerative diseases, particularly tauopathies.

Flu and Pneumonia Vaccines Linked to Reduced Risk of Alzheimer's

Good news! Every September since about 2003, I get my flu shot! It may also help against Covid-19!



"People who had gotten at least one flu shot after age 60 were 17 percent less likely to receive a subsequent diagnosis of Alzheimer’s, and those who got a flu shot each year saw their risk drop by a further 13 percent. The sooner after 60 that someone received a flu shot, the stronger the benefit."

Well, I started my regular flew shots in my early 50s!



Flu and Pneumonia Vaccines Linked to Reduced Risk of Alzheimer's | The Scientist Magazine® The authors propose that the shots might keep the immune system primed to battle diseases that would otherwise contribute to cognitive decline.

Plasticity May Make Neurons Vulnerable to Alzheimer’s Disease

This is surprising and disturbing news! Have we not considered neuroplasticity to be beneficial for many years? It helps e.g. many stroke victims to recover at least partially if not almost fully.

I have a suspicion that the neuroplasticity referred to in the article below is not the same I referred to above or that the author of this article erred when he/she used "plasticity" in the title of the article.

"Neurons that regularly remodel are more prone to Alzheimer’s disease and die when that remodeling goes awry, a new study suggests. ... Using a machine learning framework that integrated neuron type-specific mouse experiments with human studies, the researchers compared two types of neurons susceptible to Alzheimer’s with five resistant types. The most significant difference was that the vulnerable neurons were enriched with processes related to remodeling connections with adjacent neurons. ..."

Plasticity May Make Neurons Vulnerable to Alzheimer’s Disease Neurons that regularly remodel are more prone to the dysfunctions linked to the disease’s onset, a new experimental and computational study finds.

APOE Mutation Linked to Protection From Alzheimer's: Case Study

Good news (but dated from Nov. 2019)! Apparently, a woman in Colombia, who died in her 70s, had basically two opposing mutations. One of her mutations should have caused early onset of Alzheimers at around age 40, but she did not develop Alzheimer until her death due to a kind of offsetting, simultaneous mutation that protected her.

"The woman at the center of the study possesses a mutant version of PSEN1, a gene coding for a protein involved in processing amyloid precursor protein (APP) and other peptides. The variant is strongly associated with early-onset Alzheimer’s, with people showing signs of cognitive impairment by their mid-40s, and dementia by the time they’re 50. ... Using brain imaging, researchers found that the woman had extremely high levels of amyloid in her brain by the time she reached 70. However, she had little in the way of other signs of Alzheimer’s pathology, such as neurodegeneration or an accumulation of tau protein.  

“It actually illustrates ... for the first time, a very clear dissociation of amyloid accumulation from tau pathology, ... she possessed two copies of a rare mutation in APOE, another gene associated with Alzheimer’s risk. ... using in vitro experiments that the sequence, known in the scientific literature as the Christchurch variant, stops the protein product of the gene from binding strongly to its usual targets—sugar molecules involved in the accumulation of tau and neuron damage—and could thus have had a protective effect.  "



APOE Mutation Linked to Protection From Alzheimer's: Case Study | The Scientist Magazine®: A woman whose DNA suggested she'd develop early-onset dementia staved off cognitive decline for decades.

A woman’s genetic mutation may hold the key to stopping Alzheimer’s

Good news! Very recommendable! Fascinating research!

Thanks to a family in Medellin, Colombia we know now much more about Alzheimer's. "The Colombian family, 5,000 members strong, includes an estimated 1,000 or so people who carry the Paisa mutation in the presenilin 1 gene. "

"Perhaps this unusually resilient woman in Colombia shows a way to halt the disease, or at least slow it down."

"This pileup [of amyloid] is already visible in brain scans of people in their 20s who carry the mutation. By their mid-40s, many of these people have trouble remembering; they typically develop full-blown dementia by age 50.

Inheriting just one copy of the mutation is enough to lead to excess amyloid, and ultimately dementia."

A woman’s genetic mutation may hold the key to stopping Alzheimer’s | Science News: A single mutation in a woman who evaded Alzheimer’s may point to new ways to treat the disease.

Viruses Cause Extensive Neurodegenerative Diseases?

Posted: 3/3/2019

https://blogs.scientificamerican.com/artful-amoeba/the-case-for-transmissible-alzheimers-grows/?utm_source=newsletter&utm_medium=email&utm_campaign=weekly-review&utm_content=link&utm_term=2019-02-13_top-stories

Disclaimer

If confirmed and substantiated, then this is a huge discovery! This has the potential of a paradigm shift or scientific revolution! I am not a scientist or doctor!

Scientists Many Failures Are All Too Human!

Have indeed scientists and doctors seriously underestimated or even arrogantly dismissed viruses like flu for decades? For several decades, neurodegenerative diseases like Alzheimer's or Multiple Sclerosis were a mystery to our best scientists and doctors!

As an example, already as early as 1991 it was discovered that HIV traverses the blood brain barrier and causes damage to the brain and “that when the virus infiltrates the brain, it spurs neuronal death and a loss of synaptic connections” (Source 1; emphasis added). Why was this stunning discovery not immediately exploited and pursued to the fullest extent and immediately applied to other viruses?

It is very shocking to learn again and again how the best scientists and doctors can go down blind alleys for decades or even centuries ignoring or dismissing or wrongly and vigorously contesting other, alternative explanations!

Viruses And The Brain

Here is an excellent and comprehensive article about it. Usually, I am a bit reluctant to rely too much on one article to make bold generalizations, but having previously read many other reports about viruses in the brain, prions etc. I don’t think it is far fetched.

The article makes following bold statements:

1. That viruses like flu (e.g. H1N1, H5N1, herpes, HIV, encephalitis, measles) cause direct or indirect (via e.g. inflammation or toxins in compromised immune systems or via primed nervous system or via induced gene expression) damage to various brain cells (e.g. in the substantia nigra, oligodendrocytes) resulting in severe neurodegenerative symptoms like Parkinson’s, Alzheimer, dementia, encephalitis lethargica, and Multiple Sclerosis
2. These viruses are apparently capable of easily passing the blood brain barrier or they infiltrate the brain via major nerves like vagus nerve (via the gut) or lingual nerve (via the nose). We learn that viruses use at least three different ways to traverse the blood brain barrier: a) Direct crossing, b) Via Trojan horse or c) Immune response
3. Some of the neurodegenerative diseases caused by viruses may not be diagnosed in an individual before years or decades have passed

Shingles And Dementia

An article (Source 3) claims that a shingles infection that strikes the facial nerve important to facial movement (caused by varicella zoster virus) or shingles in the eye (“herpes zoster ophthalmicus”) can cause dementia (“The brain vessel damage that can occur with shingles is similar to what is often seen in dementia”). “Varicella zoster virus lives in about 95 percent of the U.S. adult population, thanks to ... chicken pox. ... but the virus remains, dormant in nerve cells [for the rest of your life] … Recently, scientists have learned more about the virus’s ability to infect arteries [“varicella zoster virus vasculopathy”], increasing the risk of stroke or causing headaches and vision problems. … One recently discovered viral target is the gut. ... the virus haunts the digestive organs’ local system of nerves, known as the enteric nervous system. In the gut, instead of a rash, the virus can cause abdominal pain, ulcers or other problems … detected varicella zoster virus in the saliva of six of 11 patients with unexplained abdominal pain for up to four months … The reactivated virus may also be behind some cases of a painful inflammation of the arteries at the temples called giant cell arteritis. More common in older adults, the disorder causes severe headaches, jaw pain and vision problems, and can lead to blindness. … But surprisingly, the virus appears to hide in very few nerve cells. In autopsy samples of ganglia …, researchers found dormant virus in only 34 of 2,226 [different?] nerve cells, or 1.5 percent” (Source 3; emphasis added).

There is more great information in the article (Source 3)!

Misfolded Proteins And The Brain

Another article (Source 4) claims that amyloid is similar and transmissible like prions. Latest research experimentally confirmed such transmission. “When the misfolded versions [of Amyloid beta] form, they behave like prions, catalyzing the conversion of healthy forms into diseased ones and accumulating in clumps called plaques. … In Parkinson’s Disease, misfolded alpha-synuclein proteins spread through the brain, and in Amyotrophic Lateral Sclerosis (Lou Gehrig’s Disease), the misfolded, accumulating protein is TDP-43. We should investigate the transmission potential of these diseases as well. … What is the difference between amyloid and prions? Are they part of a spectrum? Are they one and the same? If not, what is the difference?” (Source 4; emphasis added)

What is it now viruses or transmissibility of amyloid or both?

Sources:

1. Can the Flu and Other Viruses Cause Neurodegeneration? Scientists may need to seriously reconsider the cast-aside hypothesis that pathogens can play a part in diseases such as Alzheimer’s and Parkinson’s (published 3/1/2019)
2. PSYCHOSES ASSOCIATED WITH INFLUENZA (published 1919; this link is provided in Source 1, but I listed it separately to stress that we had for several centuries repeated hints of a link between influenza and psychic disorders, which was summarized in this 1919 article)
3. With its burning grip, shingles can do lasting damage When varicella zoster reawakens, it wreaks a surprising amount of havoc in the body (published 2/26/2019)
4. The Case for Transmissible Alzheimer's Grows What separates a lethal prion from a dementia-associated amyloid plaque? Maybe not much (published 2/7/2019; what bothers me about this article is that the author, Jennifer Frazer, wrote it in such a way that the reader is led to believe she is a researching scientist, she is not)