Alzheimer's Disease as Innate Autoimmunity

The failure of amyloid-β clearance via immunotherapy to produce benefits in Alzheimer's disease patients has spurred a great deal of theorizing, attempts to find a new way forward. Most researchers, from a survey of the field, continue to believe that amyloid-β aggregation is an important contributing factor in at least the early development of Alzheimer's. However, an increasing emphasis on immune dysfunction and chronic inflammation is creeping into modified versions of the amyloid cascade hypothesis, alongside different interpretations of the role of amyloid-β in this process, based on its participation in the innate immune response as an anti-microbial peptide.

The role of amyloid-β (Aβ) in Alzheimer's disease (AD) is debated: some argue Aβ takes center stage as the principal actor; others contend it is merely a spectator in the pageant of pathologies that typify AD. Nonetheless, a diversity of data (including in vitro neurotoxicity studies and genetic linkage analyses) do compellingly link Aβ to AD's pathology. Accordingly, rather than unconditionally rejecting the role of Aβ (or any other proposed specific disease mechanism), the need for an innovative broadly encompassing model of AD, which harmonizes multiple divergent theories into a single unified comprehensive explanation, emerges as a much-needed milestone on the road to a cure.

Herein, such a broad new molecular-level model of AD is proposed: "Alzheimer's disease as an autoimmune disease" ("AD-squared" or "AD2"). In the AD2 model, AD is explained as a brain-centric disorder of innate immunity involving concurrent autoimmune and autoinflammatory mechanisms. Although AD2 still includes Aβ as an important molecular player, it rejects the "amyloid misfolding hypothesis" per se, instead recognizing Aβ as a physiologically oligomerizing cytokine-like immunopeptide, which is merely one part of a much larger, comprehensive, highly interconnected immunopathic conceptualization of AD.

The AD2 model may be summarized as follows: in response to diverse pathogen-associated molecular pattern (PAMP) and damage-associated molecular pattern (DAMP) immune-stimulating events (e.g., infection, trauma, ischemia, air pollution, depression), Aβ is physiologically biosynthesized and released as an early responder immunopeptide, and triggers an innate immunity cascade in which oligomeric Aβ exhibits both immunomodulatory and antimicrobial properties. The immunomodulatory properties of Aβ (mediated via Aβ's oligomeric interactions with TREM2, glycosaminoglycan, and NLRP3 receptors) augment ongoing microglial activation and pro-inflammatory cytokine release thereby ultimately contributing to apoptotic neuronal death via non-specific autoinflammatory processes in which bystander neurons are killed.



The repeated failure of any research surrounding Amyloid-B should be the clearest indicator that Amyloid-B theories are bogus. I cannot believe the medical community is still pursuing Amyloid=B stuff despite repeated failures. They need to move on.

Posted by: Abelard Lindsey at October 4th, 2022 11:17 AM
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