A nonlinear meccano for Alzheimer's emergence by amyloid β-mediated glutamatergic hyperactivity

• Published in: Neurobiology of disease 2024-05, Vol.194, p.106473-106473, Article 106473
• Main Authors: Bonifazi, Giulio, Luchena, Celia, Gaminde-Blasco, Adhara, Ortiz-Sanz, Carolina, Capetillo-Zarate, Estibaliz, Matute, Carlos, Alberdi, Elena, De Pittà, Maurizio
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Amyloid-β; Astrocytes; Biophysical modeling; Circuit dysfunction; Excitotoxicity; Glutamate transporters; Hyperactivity; Vicious cycle
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2024.106473

The pathophysiological process of Alzheimer's disease (AD) is believed to begin many years before the formal diagnosis of AD dementia. This protracted preclinical phase offers a crucial window for potential therapeutic interventions, yet its comprehensive characterization remains elusive. Accumulating evidence suggests that amyloid-β (Aβ) may mediate neuronal hyperactivity in circuit dysfunction in the early stages of AD. At the same time, neural activity can also facilitate Aβ accumulation through intricate feed-forward interactions, complicating elucidating the conditions governing Aβ-dependent hyperactivity and its diagnostic utility. In this study, we use biophysical modeling to shed light on such conditions. Our analysis reveals that the inherently nonlinear nature of the underlying molecular interactions can give rise to the emergence of various modes of hyperactivity. This diversity in the mechanisms of hyperactivity may ultimately account for a spectrum of AD manifestations. •The amyloid β-mediated vicious cycle of glutamatergic hyperactivity is nonlinear.•Nonlinearities account for multiple ways for Alzheimer's emergence.•Alzheimer's pathological markers could be reverted in some hyperactivity scenarios.•Some onset scenarios require measuring both amyloid-β and glutamatergic activity.