Longevity Briefs: How The Brain’s Housekeeper Cells Malfunction In 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:

Amyloid beta plaques are masses of misfolded proteins that accumulate in the brain, and were long believed to be the cause of Alzheimer’s disease based on the finding that people who died with the disease had amyloid plaques in their brains. However, it turns out that some people who are completely cognitively intact are found to have large amounts of amyloid deposition when their brains are studied after death. In fact, some people die free of Alzheimer’s in their 80s, 90s or even 100s, despite having more amyloid plaque than people who get Alzheimer’s in their 60s and 70s.

Multiple explanations have been proposed for this observation. For example, it is possible that some people are less affected by amyloid plaque because they have more ‘cognitive reserve’ – they have healthier brains to begin with and so can afford to lose more cognitive function without getting disease. It is also possible that the amount of amyloid plaque is not what is important, but rather the rate of the underlying formative processes. If those processes are slow, you will gradually build amyloid without getting Alzheimer’s, but if they are rapid, the brain’s capacity to protect against disease is overwhelmed. Yet another theory is that amyloid plaque is an initiating factor, but it is the way the brain responds to the plaque that determines whether you get Alzheimer’s or not. In this study, researchers provide evidence for the latter, with a particular focus on how microglia – the ‘housekeeping’ immune cells within the brain – respond to amyloid.

The discovery:

Researchers collected samples from the post-mortem brains of 24 octogenarians (people who died in their 80s) and 20 centenarians (people who lived past 100). Researchers then matched samples according to the extent of amyloid deposition, sex, and ApoE variant (ApoE being the most important common genetic risk factor for Alzheimer’s). In this way, researchers could try to investigate why one person might get Alzheimer’s while someone else with the same genetic risk and amyloid deposition might die Alzheimer’s-free, potentially even decades later.

To this end, they performed RNA sequencing of brain cells, which is a way of examining the level of activity of different genes, providing a detailed snapshot of their function and state. The researchers found that microglia (cells that nurture or prune synaptic connections within the brain and are therefore vital for cognitive function, learning and memory) could have different gene expression responses to amyloid beta. The researchers termed these responses plaque induced gene programs, or PIGs. Microglia appeared to have initially responded to amyloid plaque by activating inflammatory genes – a response termed early PIGs. In octogenarians who had amyloid plaques but didn’t develop Alzheimer’s, those microglia remained in the early PIG state. However, in those who did develop Alzheimer’s in their 80s, microglia progressed towards a late PIG response and became antigen-presenting cells (a state in which cells present pathogen-associated molecules to other immune cells like T cells in order to activate them). This progression towards late PIGs correlated with increased deposition of tau – another misfolded protein that accumulates inside cells in Alzheimer’s.

Interestingly, the centenarians without Alzheimer’s had a different response to amyloid plaques – their microglia did progress to late PIG, but they somehow avoided Tau deposition and did not get Alzheimer’s. This suggested that the late PIGs don’t always lead to Alzheimer’s. In some people, late PIGs do not result in tau accumulation and they are able to live to advanced ages without getting disease. In others, early PIG microglia rapidly transition to late PIG in conjunction with tau accumulation, and this appears to correlate with Alzheimer’s.

The implications:

It appears from this study that the way microglia respond to amyloid plaque may be important for determining whether someone gets Alzheimer’s disease. Early on, microglia respond with inflammation, which may indicate they are working to clear amyloid from the brain. However, in the subjects of this study who developed Alzheimer’s in their 80s, those microglia quickly progressed to an antigen-presenting state, while those who avoided Alzheimer’s retained their early state microglia. Centenarians, on the other hand, did not seem to suffer from having late PIG microglia. It seems that the overall response of the brain to amyloid is complex and variable between individuals, and this may be what determines whether someone will get Alzheimer’s in response to amyloid.

This study was observational in nature, so it cannot prove causation – it is possible that those who progressed to late PIGs simply had a more severe form of the disease, and that microglia behaviour is just a symptom of this. Since brains were matched for amyloid deposition and ApoE variants, the comparisons being made should have been between brains with similar disease severity. However, the causes of Alzheimer’s disease are still poorly understood, and there may be components of disease severity that we don’t know about.