Alzheimer's disease as an innate autoimmune disease (AD²): A new molecular paradigm

Abstract

A new model of Alzheimer's disease (AD) is presented: Alzheimer's disease as an autoimmune disease (AD 2 ). In response to pathogen-/damage-associated molecular pattern-stimulating events (e.g., infection, trauma, ischemia, pollution), amyloid beta (Aβ) is released as an early responder cytokine triggering an innate immunity cascade in which Aβ exhibits immunomodulatory/antimicrobial duality. However, Aβ's antimicrobial properties result in a misdirected attack upon "self" neurons, arising from the electrophysiological similarities between neurons and bacteria in terms of transmembrane potential gradients and anionic charges on outer membrane macromolecules. The subsequent breakdown products of necrotic neurons elicit further release of Aβ leading to a chronic, self-perpetuating cycle. In AD 2 , amino acid (trp, arg) metabolism is a central control player in modulating AD autoimmunity. AD 2 includes Aβ as an important molecular player, but rejects the "amyloid hypothesis," recognizing Aβ as a physiologically oligomerizing cytokine and part of a larger immunopathic conceptualization of AD.

Gene- and Gender-Related Decrease in Serum BDNF Levels in Alzheimer’s Disease

“…[ 69 ]. Recently, a new model of AD as an autoimmune disease of innate immunity has been theorized, in which Aβ would act as a cytokine-like immunopeptide, the target of an innate autoimmune response that fuels an auto-inflammatory process [ 70 ]. In this model, the modulation of endogenous anti-AD molecules would have a central therapeutic role.…”

When the microbiome helps the brain‐current evidence

“…Recently, poor gut microbiota diversity in AD patients has gained an ongoing interest followed by finding an additional molecular pathogenesis for AD. Novel findings suggest that autoimmune and autoinflammatory mechanisms are engaged in AD 99 . The data suggested that SCFAs, such as butyric, propionic, acetic acids, and microbial metabolites in colon reduced the AD neuropathological features and other neurodegenerative diseases by providing alternative energy sources to the brain 100 .…”

Sex and Gender Differences in Neurodegenerative Diseases: Challenges for Therapeutic Opportunities

“…The hallmark features of AD include the presence of extracellular amyloid-β plaques (Aβ), intracellular neurofibrillary tangles, and neurodegeneration. Of interest, AD is described as a brain-centric disorder of innate immunity involving simultaneous autoimmune and autoinflammatory mechanisms [ 70 ]. In response to initial (yet unknown) stimuli, Aβ is released as an early reactive immunopeptide, exhibiting both immunomodulatory and antimicrobial properties (in the presence or absence of bacteria), and triggering an innate immune cascade that causes a misdirected attack against “self” neurons.…”