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The nonlinear meccano of hyperactivity in Alzheimer

Bonifazi, G.; Luchena, C.; Gaminde-Blasco, A.; Ortiz-Sanz, C.; Capetillo-Zarate, E.; Matute, C.; Alberdi, E.; De Pitta, M.

2023-10-10 neuroscience
10.1101/2023.10.09.561541 bioRxiv
Show abstract

The pathophysiological process of Alzheimers 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-{beta} (A{beta}) may mediate neuronal hyperactivity in circuit dysfunction in the early stages of AD. At the same time, neural activity can also facilitate A{beta} accumulation through intricate feed-forward interactions, complicating elucidating the conditions governing A{beta}-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 various modes of hyperactivity emergence. This diversity in the mechanisms of hyperactivity may ultimately account for a spectrum of AD manifestations.

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