THE ROLE OF AΒ IN ALZHEIMER’S DISEASE AS AN EVOLUTIONARY OUTCOME OF OPTIMIZED INNATE IMMUNE DEFENSE
Alzheimer’s Disease is a progressive manifestation of aging associated with accumulated Amyloid β. It remains frustratingly unclear why this protein accumulates and how it contributes to Alzheimer’s Disease pathology. In one recent hypothesis, Amyloid β is suggested to function as an antimicrobial peptide in innate immune defense within the brain, where Amyloid β gains toxicity when it becomes abundant. This essay proposes an evolutionary explanation for why Amyloid β expression is regulated at an optimum based on its function as a defense and how this leads to disease. Among its potential physiological functions, Amyloid β confers benefits to reduce direct pathogen damage while this simultaneously entails cellular cost of defense. Optimal Amyloid β expression occurs when the gain in fitness from an incremental increase is balanced by the marginal cost of this increase. It proposes that natural selection acting upon the young favored systems to maintain Amyloid β at an optimal level through mechanisms that induce the defense and repress its expression. With age, the force of natural selection declines and permits mechanisms of negative feedback repression to degenerate. Consequently, Amyloid β is expressed beyond its optimum. Age also elevates cumulative pathogen exposure, reduces pathogen barriers and reactivates latent pathogens. The net effect is elevated, chronic induction of Amyloid β in the brain. The model recommends attention to innate immune negative regulation in the brain to discover ways to restore these functions toward a youthful state in the elderly.
M. Tatar ; (2022): The role of Aβ in Alzheimer’s Disease as an Evolutionary Outcome of Optimized Innate Immune Defense. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.68