An agnostic reevaluation of the amyloid cascade hypothesis of Alzheimer's disease pathogenesis: The role of APP homeostasis

Abstract

Objective: To reassess the role of amyloid beta (Aβ) and the amyloid precursor protein (APP) system in the pathogenesis of Alzheimer's disease (AD). Background: APP is a cell adhesion molecule that has been highly conserved over the course of phylogeny that has critical roles in brain development, synaptic plasticity, and the brain's intrinsic immune system. The amyloid cascade hypothesis describes a relatively linear, deterministic sequence of events triggered by a gain of Aβ peptide fragment toxicity that results in neurodegeneration and cognitive loss, yet well designed immunotherapy and beta secretase inhibitor trials that have successfully targeted Aβ have failed to have any consistent effects on the steady decline of cognition. New/updated hypothesis: Mutations of the APP and presenilin genes not only alter the ratio of longer to shorter Aβ fragments (resulting in a gain of Aβ toxicity), but also disrupt the normal homeostatic roles of their respective proteins. The evolutionary history, physiological importance, and complexity of the APP and presenilin systems, as well as other critical components including tau and apolipoprotein E (APOE) imply that altered function of such systems could have severe consequences that include but need not be limited to a gain of Aβ toxicity and would more generally result in altered homeostasis of APP-related functions. Major challenges addressed by our hypothesis: Challenges that a loss of APP homeostasis addresses better than the more limited gain of Aβ toxicity model include the topographic mismatches between Aβ and tau pathology, the profile and chronology of cognitive and biomarker changes that precede the clinical expression of mild cognitive impairment and dementia, and the disappointments of Aβ targeted therapeutics among others. Linkage to other major theories: The importance of APP, αand β-secretases, the presenilins and γ-secretase, as well as tau was recognized by the authors of the amyloid cascade hypothesis, and has since led multiple investigators to propose alternative, more balanced hypotheses including reduced homeostasis and frank loss-of-function of key components that include but go beyond the currently envisioned linear model of Aβ toxicity.

ER Stress-Sensor Proteins and ER-Mitochondrial Crosstalk—Signaling Beyond (ER) Stress Response

“…AD is most commonly seen in elderly people and is associated with the formation of intracellular tangles of hyperphosphorylated tau and formation of plaques by beta-amyloid peptides, due to the cleavage of amyloid precursor proteins by beta and gamma-secretase which has a core dimer of Presenilin 1 and 2 (PS1, PS2) [181]. It is found that PS1 and PS2 are enriched at MAM and affect the communication between ER and mitochondria.…”

Alzheimer's disease: An evolving understanding of noradrenergic involvement and the promising future of electroceutical therapies

“…1,[98][99][100] The amyloid cascade hypothesis continues to undergo serial iterations, and the most recent adaptation hypothesizes that Aβ accumulation is part of a broader alteration in the homeostasis of APPrelated functions. 101…”

Peptides Derived from Growth Factors to Treat Alzheimer’s Disease

“…Consequently, many clinical trials have been directed toward Aβ-lowering strategies, including interference with the amyloidogenic processing of APP, mainly with β- and γ-secretase inhibitors, and removing Aβ oligomers and plaques with monoclonal antibodies [ 22 , 27 ]. Unfortunately, until now, no therapy directed at reducing Aβ has been successful, resulting in either no cognitive benefit, or even worsening cognitive outcome or inducing major side effects [ 28 , 29 , 30 , 31 ]. However, a recent phase 2 trial of Donanemab, a humanized IgG1 antibody that targets a modified form of Aβ present only in established plaques, showed modest inhibition of cognitive and functional decline in early symptomatic AD patients [ 32 ].…”