How Your Brain Manages Cholesterol Could Increase Alzheimer’s Risk

Alzheimer’s disease is characterized by a host of recognizable cognitive symptoms, but many non-cognitive symptoms like changes in sleep, anxiety and depression can be early signs of the disease. These symptoms can appear decades prior to the onset of cognitive decline, but the mechanisms underlying degeneration at these stages is unclear.

Biologically speaking, Alzheimer’s is characterized by the progression of amyloid-beta plaques and tau-positive neurofibrillary tangles, the latter of which are closely associated with loss of neurons in the brain. Understanding why and how specific neurons are affected by Alzheimer’s while others aren’t is a key challenge.

To understand what makes some neurons more vulnerable than others at the earliest stages of Alzheimer’s, researchers at the UC San Francisco Memory and Aging Center examined brain tissue samples from two brain regions with differing susceptibility. They were surprised to find that the brain’s cholesterol regulation mechanisms may be a factor underlying vulnerability.

The study appears March 26, in Alzheimer’s & Dementia: The Journal of the Alzheimer's Association. 

Potential therapeutic targets for early Alzheimer's

Using the resources of two brain banks, the Neurodegenerative Disease Brain Bank at UCSF and the Biobank for Aging Studies at the University of São Paulo, the researchers gathered a large collection of brain tissue samples from deceased patients and compared two different brain regions within the same individual: one region without any disease changes and the other in the earliest stages of Alzheimer’s-type neurodegeneration. 

Then, from each brain, they collected a sample of the noradrenaline-producing locus coeruleus (LC) – a region that is highly vulnerable to Alzheimer’s – and the dopamine-producing substantia nigra (SN) – a region resistant to Alzheimer’s degeneration the researchers then analyzed RNA from the different brain regions to measure the expression levels of different genes. They used this gene expression data to provide a full picture of which cellular processes vary between these two neuronal populations.

“These two regions are remarkably similar despite their markedly different vulnerabilities to Alzheimer’s Disease,” said study first author Alexander Ehrenberg, PhD, an investigator at the UCSF Memory and Aging Center and translational health fellow at the Innovative Genomics Institute. “Both are anatomically and neurochemically similar, and both are also similarly vulnerable to other neurodegenerative diseases like Parkinson’s. Given this, we reasoned that the differences between the brain regions at the beginning of the study would offer clues into the baseline selective vulnerability of the LC to Alzheimer’s disease.”

Their results showed a striking segregation between the LC and SN in how they regulate cholesterol levels. “One key difference between the brain regions had to do with cholesterol metabolism and homeostasis,” said Ehrenberg. “The LC neurons exhibit signatures suggesting that they are super cholesterol-hungry – these neurons are doing both their best to produce their own cholesterol and take in as much as possible. The SN, on the other hand, doesn’t have the same level of demands.”

Using immunohistochemistry tissue staining – the gold standard to demonstrate proteins at single cell level in tissue from different cases – the researchers validated these findings. They found that the LC neurons express higher levels of LDLR, part of a receptor called sigma-2 that helps cells take in cholesterol molecules. A consequence of this is that toxic amyloid-beta oligomers (small clumps of amyloid-beta protein) may “sneak in” to the neurons via this same receptor. Conversely, the SN expresses a selective degrader of LDLR, making it less susceptible to these oligomers.

This finding, as well as differences in heavy metal processing and other gene sets that may contribute to the vulnerability of the LC compared to the SN in Alzheimer’s, highlight potential therapeutic targets for early treatment of this disease.

“The study highlights how cholesterol regulation not only explains differences between people’s vulnerability to Alzheimer’s, but also differences in vulnerability between brain regions at early disease stages,” said senior author Lea Grinberg, MD, PhD, the John Douglas French Alzheimer’s Foundation Endowed Professor at the UCSF Memory and Aging Center. “A deeper understanding of the causal factors underlying LC degeneration – and the development of strategies to mitigate its vulnerability – could have a profound impact on the treatment of AD. LC dysregulation impairs critical functions such as sleep regulation and neuroinflammatory control, both of which are recognized as key risk factors that can accelerate AD progression.”

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