There is no shortage of theorizing in the Alzheimer's disease community. The lengthy failure of therapies targeting amyloid-β, first the failure to clear amyloid-β meaningfully, and then the failure to produce benefits in patients after clearance was achieved, has led to a great deal of frustration and the search for new views of the condition that might lead to different therapeutic strategies. Many of these viewpoints should probably be taken with a grain of salt (e.g. that modern painkillers play an important role), while others are quite compelling (e.g. persistent viral infection, or the burden of cellular senescence in supporting cells in the brain). Today's example is an interesting reframing of what is known of the role of amyloid-β in the innate immune system, and how that might apply to Alzheimer's disease.
As new potentially explanatory biochemical mechanisms for Alzheimer's disease (AD) emerge, they are often regarded as mutually exclusive and in competition - a situation resulting in pronouncements that the amyloid hypothesis, plagued by numerous clinical trial failures, is dead and needs to be replaced. However, a variety of data compellingly link amyloid beta (Aβ) to the pathogenesis of AD. Accordingly, rather than categorically rejecting the role of Aβ, the need for a new widely encompassing conceptualization of AD that unifies seemingly divergent theories into a single harmonized explanation emerges as an effective strategy. Incorporating protein misfolding mechanisms into a broader-based immunopathic model of AD could attain such a goal - a goal which can be achieved by repositioning Aβ as an immunopeptide.
In response to various stimuli (e.g., infection, trauma, ischemia, air pollution, depression), Aβ is released as an early responder immunopeptide triggering an innate immunity cascade in which Aβ exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not), resulting in a misdirected attack upon neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membrane-penetrating attack by antimicrobial peptides (AMPs) such as Aβ. After this self-attack, the resulting necrotic (but not apoptotic) neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aβ, leading to a chronic self-perpetuating autoimmune cycle. AD thus emerges as a brain-centric autoimmune disorder of innate immunity.
Based upon the hypothesis that autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of 1137 small molecules normally present in the human brain identified tryptophan metabolism as a regulator of brain innate immunity and a source of potential endogenous anti-AD molecules capable of chemical modification into multi-site therapeutic modulators targeting AD's complex pathogenesis.