A New Bistable Switch Model of Alzheimer’s Disease Pathogenesis

Abstract

We propose a model to explain the pathogenesis of Alzheimer’s disease (AD) based on the theory that any disease affecting a healthy organism originates from a bistable feedback loop that shifts the system from a physiological to a pathological condition. We focused on the known double inhibitory loop involving the cellular prion protein (PrPC) and the enzyme BACE1 that produces amyloid-beta (Aβ) peptides. BACE1 is inhibited by PrPC, but its inhibitory activity is lost when PrPC binds to Aβ oligomers (Aβo). Excessive Aβo formation would switch the loop to a pathogenic condition involving the Aβo-PrPC-mGluR5 complex, Fyn kinase activation, tau, and NMDAR phosphorylation, ultimately leading to neurodegeneration. Based on the emerging role of cyclic nucleotides in Aβ production, and thereby in synaptic plasticity and cognitive processes, cAMP and cGMP can be considered as modulatory factors capable of inducing the transition from a physiological steady state to a pathogenic one. This would imply that critical pharmacological targets for AD treatment lie within pathways that lead to an imbalance of cyclic nucleotides in neurons. If this hypothesis is confirmed, it will provide precise indications for the development of preventive or therapeutic treatments for the disease.

Kinetic Model With Feedback Cycle for Age-Dependent Beta Amyloid Accumulation in Mice

“…The positive feedback models proposed earlier by Dupont and De Caluwé [6], and more schematically by Burlando et al [21], similar in some ways to ours, show bistability with a "jump" from a healthy to unhealthy state. This is not the picture seen in our model, which is more like a lifelong steady "drift."…”

“…The positive feedback models proposed earlier by Dupont and De Caluwé [6], and more schematically by Burlando et al . [21], similar in some ways to ours, show bistability with a “jump” from a healthy to unhealthy state. This is not the picture seen in our model, which is more like a lifelong steady “drift.” We are focused on a transgenic mouse strain designed to demonstrate extreme Aβ accumulation, and the question of bistability might be different in an examination of analogous human data, if and when they become available.…”

“…They suppose a "jump" from a healthy to a diseased state, associated with a critical point of bistability in their kinetic model. A similar idea of a bistable jump model is outlined schematically by Burlando et al [21]. Does such a picture pertain to the model considered here?…”

“…A similar idea of a bistable jump model is outlined schematically by Burlando et al . [21]. Does such a picture pertain to the model considered here?…”

Amyloid-β Effects on Peripheral Nerve: A New Model System

“…Some studies have suggested signaling pathways by which this might occur. These include m-RNAbased amplification of amyloid precursor protein production [60], feedback loops involving acetylcholine receptors (α7-nAchR) [61], or complex non-linear dynamics involving the prion protein PRP C and cyclic nucleotides [62].…”