Longevity Briefs: Why Do Parts Of The Brain Escape Alzheimer’s?

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

What do obesity, atherosclerosis and Alzheimer’s disease all have in common? They all involve low density lipoprotein, or LDL. Somewhat confusingly referred to as ‘bad cholesterol’, LDL is a membrane package that contains primarily cholesterol, but also some triglycerides (fats). In obese individuals, the body produces too much LDL. In atherosclerosis, LDL is absorbed by the walls of the blood vessels within which its cholesterol becomes trapped, resulting in the formation fatty plaques. LDL appears to contribute to Alzheimer’s disease in several ways. The famous ApoE4 gene variant, two copies of which will increase the risk of Alzheimer’s disease by around 15 fold, encodes a receptor for LDL.

It now appears as though LDL processing in the brain may help explain a long-unsolved mystery: why are some regions of the brain devastated by Alzheimer’s disease, while others are left relatively unscathed.

The discovery:

In this study, researchers examined post-mortem brain samples from 22 Alzheimer’s patients with no other neurodegenerative diseases, and with an average age at death of 64 years. They then measured gene expression in two brain regions: the locus coeruleus (LC), which is one of the first regions to show signs of Alzheimer’s damage, and the substantia nigra (SN), which is much more resilient. The authors picked these two regions because aside from their vulnerability to Alzheimer’s, they are very similar to each other and are also similarly vulnerable to other neurodegenerative diseases.

They found that there were substantial differences in the expression of genes related to cholesterol processing between the two regions. The LC – the more severely affected region – appeared to be much more cholesterol-hungry, expressing genes involved in LDL uptake and the production of new cholesterol within LC cells. This included increased production of a piece of the Sigma-2 receptor complex, which not only transports LDL into cells, but also absorbs soluble amyloid beta – the misfolded protein that accumulates in the brains of Alzheimer’s patients. These characteristics were also detected in the patients who died during the early stages of Alzheimer’s. The SN, on the other hand, showed the opposite trend, including an increased transport of cholesterol out of its cells.

The implications:

This research suggests that while differences in cholesterol processing could explain why some people are more at risk of Alzheimer’s, it may also explain why some specific brain regions are more vulnerable. A higher uptake of LDL to support a higher demand for cholesterol may provide a ‘back door’ for amyloid beta to enter the cell, as well as the accumulating cholesterol impairing function through other previously established mechanisms. As for why the LC is more cholesterol-hungry, all neurons require cholesterol to maintain their membranes and myelin sheath – the fatty coating that wraps around some nerve fibres to speed up the transmission of electrical impulses. The LC has much longer, more extensive projections to different brain regions, so this increased cholesterol demand may simply come down to having more projections to support. The LC has many functions including regulating sleep, which is disrupted in the very earliest stages of Alzheimer’s and probably has a two-way relationship with the disease (that is to say, poor sleep promotes Alzheimer’s and vice-versa).

It’s important to note that this was quite a small exploratory study that only compared LC and SN to each other within individual brains – they did not compare these regions to those from healthy brains. It’s therefore not certain to what extent the cholesterol metabolism in the LC of these patients was abnormal. It could be that even in healthy brains, cholesterol metabolism in the LC is ramped up, making it more vulnerable to Alzheimer’s disease. Alternatively, perhaps some of these differences emerge as Alzheimer’s develops. Either way, hopefully a greater understanding of the role of cholesterol metabolism in the brain will eventually enable us to target it directly in some way. There is already some evidence that cholesterol-lowering drugs, namely statins, reduce Alzheimer’s risk. LDL levels, which are modifiable through diet and exercise, are estimated to be responsible for 7% of all dementia cases, not just Alzheimer’s. A lot of this will be due to the relationship between dementia and cardiovascular disease – another highly undesirable set of conditions.