Positive Feedback Loops in Alzheimer's Disease: The Alzheimer's Feedback Hypothesis

Abstract

The dominant model for Alzheimer's disease (AD) is the amyloid cascade hypothesis, in which the accumulation of excess amyloid-β (Aβ) leads to inflammation, excess glutamate and intracellular calcium, oxidative stress, tau hyperphosphorylation and tangle formation, neuronal loss, and ultimately dementia. In a cascade, AD proceeds in a unidirectional fashion, with events only affecting downstream processes. Compelling evidence now exists for the presence of positive feedback loops in AD, however, involving oxidative stress, inflammation, glutamate, calcium, and tau. The pathological state of AD is thus a system of positive feedback loops, leading to amplification of the initial perturbation, rather than a linear cascade. Drugs may therefore be effective by targeting numerous points within the loops, rather than concentrating on upstream processes. Anti-inflammatories and anti-oxidants may be especially valuable, since these processes are involved in many loops and hence would affect numerous processes in AD.

Keywords: Aggregation; amyloid; amyloid-β protein precursor; directed acyclic graph; drug discovery; peptide; systems biology.

Fig.1

The Amyloid cascade.

Fig.2

Feedback Loops in the Amyloid Cascade. Blue arrows show pathways in healthy cells; black arrows show AD pathways; pathways activated in AD are in green; pathways inhibited in AD are in red. The dashed line shows a tentative connection from hyperphosphorylated τ to increased AβPP processing to Aβ.