Depletion of Microglia Greatly Reduces Tau Pathology in Mouse Models of Alzheimer's Disease

Today's research adds to the body of work supporting a vital role for microglia in the progression of Alzheimer's disease from early stages characterized by amyloid-β aggregation and mild cognitive impairment to later stages characterized by tau aggregation and severe neurodegeneration. Microglia are one of the classes of supporting immune cell in the brain. They are similar to macrophages of the innate immune system that are present in the rest of the body, outside the central nervous system, but microglia undertake a much more varied set of tasks beyond clearing up debris, hunting pathogens, and the usual portfolio of immune cell activities. Much of the maintenance and alteration of synaptic connections between neurons is dependent on the presence of microglia, for example.

It is becoming clear that inflammatory dysfunction in microglia is a part of the growing metabolic disarray that allows tau protein to aggregate in the brain, and thereby lead to the death of neurons. It is a matter for debate as to whether this occurs because of amyloid-β aggregation, or whether amyloid-β aggregation is just another consequence of microglial dysfunction that occurs for other underlying reasons.

Studies published earlier this year, carried out in animal models of Alzheimer's disease, suggest that cellular senescence of microglia is very influential in the progression of neurodegeneration. Some of the early senolytic drugs, such as dasatinib, can cross the blood-brain barrier, and so it is possible to test selective destruction of senescent cells in the brain as an approach to therapy. The results offer the possibility that presently available low-cost senolytics may turn out to be more effective than most present approaches to treatment of neurodegenerative conditions.

Microglia can be inflammatory without being senescent, however. Like macrophages, microglia can switch between modes of behavior, known as polarizations, with the two of greatest interest being M1, inflammatory and aggressive in pursuit of pathogens, and M2, anti-inflammatory and focused on regeneration and repair. Numerous studies have suggested that aging is characterized by excessive proportions of M1 macrophages and microglia, though exactly why this is the case - how it connects to rising levels of the underlying molecular damage of aging - remains an open question.

Targeting immune cells may be potential therapy for Alzheimer's

Under ordinary circumstances, tau contributes to the normal, healthy functioning of brain neurons. In some people, though, it collects into toxic tangles that are a hallmark of neurodegenerative diseases such as Alzheimer's. Researchers had shown that microglia limit the development of a harmful form of tau. But they also suspected that microglial cells could be a double-edged sword. Later in the course of the disease, once the tau tangles have formed, the cells' attempts to attack the tangles might harm nearby neurons and contribute to neurodegeneration.

To understand the role of microglial cells in tau-driven neurodegeneration, researchers first studied genetically modified mice that carry a mutant form of human tau that easily clumps together. Typically, such mice start developing tau tangles at around 6 months of age and exhibiting signs of neurological damage by 9 months. Then, the researchers turned their attention to the gene APOE. Everyone carries some version of APOE, but people who carry the APOE4 variant have up to 12 times the risk of developing Alzheimer's disease compared with those who carry lower-risk variants. The researchers genetically modified the mice to carry the human APOE4 variant or no APOE gene. APOE4 amplifies the toxic effects of tau on neurons.

For three months, starting when the mice were 6 months of age, the researchers fed some mice a compound to deplete microglia in their brains. Other mice were given a placebo for comparison. The brains of mice with tau tangles and the high-risk genetic variant were severely shrunken and damaged by 9 months of age - as long as microglia were also present. If microglia had been eliminated by the compound, the mice's brains looked essentially normal and healthy with less evidence of harmful forms of tau despite the presence of the risky form of APOE. Further, mice with microglia and mutant human tau but no APOE also had minimal brain damage and fewer signs of damaging tau tangles. Additional experiments showed that microglia need APOE to become activated. Microglia that have not been activated do not destroy brain tissue or promote the development of harmful forms of tau.

Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model

Chronic activation of brain innate immunity is a prominent feature of Alzheimer's disease (AD) and primary tauopathies. However, to what degree innate immunity contributes to neurodegeneration as compared with pathological protein-induced neurotoxicity, and the requirement of a particular glial cell type in neurodegeneration, are still unclear. Here we demonstrate that microglia-mediated damage, rather than pathological tau-induced direct neurotoxicity, is the leading force driving neurodegeneration in a tauopathy mouse model. Importantly, the progression of phosphorylated tau pathology is also driven by microglia.

In addition, we found that APOE, the strongest genetic risk factor for AD, regulates neurodegeneration predominantly by modulating microglial activation, although a minor role of apoE in regulating phosphorylated tau and insoluble tau formation independent of its immunomodulatory function was also identified. Our results suggest that therapeutic strategies targeting microglia may represent an effective approach to prevent disease progression in the setting of tauopathy.

Comments

I just checked out Arvinas, the leading company that develops a new class of small molecules that can in theory degrade any protein in the body. They have a Protac (preclinically) that crosses the blood brain barrier and degenerates Tau. It could well be that in a few yeas this new class of molecules will be all the rage, because all of a sudden you can target the other 80% of the proteome.

Here is a PowerPoint from Arvinas (Tau begins at slide 25) that gives a good overview
http://ir.arvinas.com/static-files/73311000-3d7d-42c9-9316-092727498cab

Posted by: Tom at October 24th, 2019 11:06 PM

@Antonio so the Peeping Toms at Biogen may have killed a 10 billion + drug pro year thanks to a futility analysis, that hurts.

Posted by: Tom at October 25th, 2019 5:34 AM

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