Towards a More Glial-Centric View of Alzheimer's Disease

The progression of Alzheimer's disease is very complicated, and yet to be fully understood, for all that there is a good catalog of the individual pathological mechanisms involved as the condition progresses: aggregation of amyloid-β and tau; persistent viral infection; chronic inflammation; dysfunction in the immune cells of the brain; and more. The question is how these mechanisms fit together into chains of cause and effect, a process of discovery that is complicated by the fact that order of progression or importance of specific mechanisms may be quite different between individuals, and some mechanisms have two-way relationships, in which either is capable of aggravating the other.

Is Alzheimer's disease a condition in which various factors cause amyloid-β deposition over the years, which causes glial cells in the brain to become dysfunctional and inflammatory, which leads to formation of the toxic tau protein aggregates known as neurofibrillary tangles and consequent cell death? Or is Alzheimer's disease due to the age-related disarray of glial cells, that in turn leads initially to amyloid-β pathology, and then later to tau pathology as the state of disarray worsens? There is good evidence to support either position. That clearing amyloid-β from the brain has failed persistently to improve patients is a strike against the amyloid-β as first cause arguments, but equally it may be that these efforts have taken place at too late a stage in the progression of Alzheimer's disease, long after it would have been effective.

Microglia in Alzheimer Disease: Well-Known Targets and New Opportunities

Microglia cells are the main immunocompetent cells in the brain. They colonize the brain in the early prenatal period, but contrary to other tissue resident macrophages, they remain secluded within the central nervous system (CNS) throughout life and self-renew at slow pace. Should the brain homeostasis be compromised, microglia change their phenotype and initiate a defense program. Thus, under pathological conditions, they adopt reactive states characterized by multiple morphological and functional changes including but not limited to increased phagocytosis and increased expression of receptors, cytokines, chemokines, and additional inflammation related molecules.

Alzheimer's disease (AD) classical hallmarks include brain atrophy, extracellular amyloid-beta (Aβ) deposits, intracellular aggregated phosphorylated tau, dystrophic neurites, synapses, and neurons loss. The presence of reactive glial cells within the neuritic plaques was described by Alois Alzheimer himself and further studies identified both reactive astrocytes and microglia in the vicinity of the Aβ deposits. Long considered as a consequence of the pathology, reactive glia and associated neuroinflammation are now regarded as playing key roles in both disease initiation and progression. Evidence strongly supports a causal involvement of microglial cells in AD pathogenesis and generated a strong interest for studying these cells. Yet, the roles of microglia in AD initiation and progression are unclear and heavily debated, with conflicting reports regarding their detrimental or protective contribution to the disease.

The involvement of microglia in AD is a relatively new area of research, but it is growing at a fast pace. Recent genome-wide association studies have established that the majority of AD risk loci are found in or near genes that are highly and sometimes uniquely expressed in microglia. This leads to the concept of microglia being critically involved in the early steps of the disease and identified them as important potential therapeutic targets.

Over the recent years, several technological breakthroughs have been achieved, allowing scientists to address new challenging questions. These technical developments now allow studying microglia roles with medium or high throughput workflows, and perform fine analysis of their functions in preserved environments. A better understanding of the contribution of microglia cells to AD initiation and progression is expected to renew the interest of big pharma to re-invest in the field and will pave the way toward better designed strategies.

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