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 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)
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.
