Brain organoid model shows molecular signs of Alzheimer’s before birth

In a model of human fetal brain development, Emory researchers can see perturbations of epigenetic markers in cells derived from people with familial early-onset Alzheimer’s disease, which takes decades to appear. This suggests that in people who inherit mutations linked to early-onset Alzheimer’s, it would be possible to detect molecular changes in their brains before birth. The results were published in the journal Cell Reports. “The beauty of using organoids is that they allow us to Read more

The earliest spot for Alzheimer's blues

How the most common genetic risk factor in AD interacts with the earliest site of neurodegeneration Read more

Make ‘em fight: redirecting neutrophils in CF

Why do people with cystic fibrosis (CF) have such trouble with lung infections? The conventional view is that people with CF are at greater risk for lung infections because thick, sticky mucus builds up in their lungs, allowing bacteria to thrive. CF is caused by a mutation that affects the composition of the mucus. Rabindra Tirouvanziam, an immunologist at Emory, says a better question is: what type of cell is supposed to be fighting the Read more

tauopathy

Unusual partnership may drive neurodegeneration in Alzheimer’s

Emory researchers have gained insights into how toxic Tau proteins kill brain cells in Alzheimer’s disease and other neurodegenerative diseases. Tau is the main ingredient of neurofibrillary tangles, one of two major hallmarks of Alzheimer’s.

Pathological forms of Tau appear to soak up and sequester a regulatory protein called LSD1, preventing it from performing its functions in the cell nucleus. In mice that overproduce a disease-causing form of Tau, giving them extra LSD1 slows down the process of brain cell death.

The results were published on November 2 in Proceedings of the National Academy of Sciences.

Blocking the interaction between pathological Tau and LSD1 could be a potential therapeutic strategy for Alzheimer’s and other diseases, says senior author David Katz, PhD, associate professor of cell biology at Emory University School of Medicine.

“Our data suggest that inhibition of LSD1 may be the critical mediator of neurodegeneration caused by pathological Tau,” Katz says. “Our intervention was sufficient to preserve cells at a late stage, when pathological Tau had already started to form.”

While the Katz lab’s research was performed in mice, they have indications that their work is applicable to human disease. They’ve already observed that LSD1 abnormally accumulates in neurofibrillary tangles in brain tissue samples from Alzheimer’s patients.

First author Amanda
Engstrom, PhD

Mutations in the gene encoding Tau also cause other neurodegenerative diseases such as frontotemporal dementia and progressive supranuclear palsy. In these diseases, the Tau protein accumulates in the cytoplasm in an aggregated form, which is enzymatically modified in abnormal ways. The aggregates are even thought to travel from cell to cell.

Tau is normally present in the axons of neurons, while LSD1 goes to the nucleus. LSD1’s normal function is as an “epigenetic enforcer”, repressing genes that are supposed to stay off.

“Usually LSD1 and Tau proteins would pass each other, like ships in the night,” Katz says. “Tau only ends up in the cytoplasm of neurons when it is in its pathological form, and in that case the ships seem to collide.”

Former graduate student Amanda Engstrom PhD, the first author of the paper, made a short video that explains how she and her colleagues think LSD1 and Tau are coming into contact.

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Posted on by Quinn Eastman in Neuro Leave a comment

Acidity of aging leads to new Alzheimer’s drug target

Pathologist Keqiang Ye and his colleagues have been studying the functions of an enzyme called AEP, or asparagine endopeptidase, in the brain. AEP is activated by acidic conditions, such as those induced by stroke or seizure.

AEP is a protease. That means it acts as a pair of scissors, snipping pieces off other proteins. In 2008, his laboratory published a paper in Molecular Cell describing how AEP’s acid-activated snipping can unleash other enzymes that break down brain cells’ DNA.

Following a hunch that AEP might be involved in neurodegenerative diseases, Ye’s team has discovered that AEP also acts on tau, which forms neurofibrillary tangles in Alzheimer’s disease.

“We were looking for additional substrates for AEP,” Ye says. “We knew it was activated by acidosis. And we had read in the literature that the aging brain tends to be more acidic, especially in Alzheimer’s.”

The findings, published in Nature Medicine in October, point to AEP as a potential target for drugs that could slow the advance of Alzheimer’s, and may also lead to improved diagnostic tools. Read more

Posted on by Quinn Eastman in Neuro Leave a comment