Circuitry and Synaptic Dysfunction in Alzheimer’s Disease: A New Tau Hypothesis

Author:

Mondragón-Rodríguez Siddhartha12ORCID,Salgado-Burgos Humberto3,Peña-Ortega Fernando2

Affiliation:

1. CONACYT National Council for Science and Technology, México, Mexico

2. UNAM Developmental Neurobiology and Neurophysiology, Institute of Neurobiology, National Autonomous University of México, Querétaro, Mexico

3. UADY Neurosciences Department, Autonomous University of Yucatán, 97000 Mérida, Yucatán, Mexico

Abstract

For more than five decades, the field of Alzheimer’s disease (AD) has focused on two main hypotheses positing amyloid-beta (Aβ) and Tau phosphorylation (pTau) as key pathogenic mediators. In line with these canonical hypotheses, several groups around the world have shown that the synaptotoxicity in AD depends mainly on the increase in pTau levels. Confronting this leading hypothesis, a few years ago, we reported that the increase in phosphorylation levels of dendritic Tau, at its microtubule domain (MD), acts as a neuroprotective mechanism that prevents N-methyl-D-aspartate receptor (NMDAr) overexcitation, which allowed us to propose that Tau protein phosphorylated near MD sites is involved in neuroprotection, rather than in neurodegeneration. Further supporting this alternative role of pTau, we have recently shown that early increases in pTau close to MD sites prevent hippocampal circuit overexcitation in a transgenic AD mouse model. Here, we will synthesize this new evidence that confronts the leading Tau-based AD hypothesis and discuss the role of pTau modulating neural circuits and network connectivity. Additionally, we will briefly address the role of brain circuit alterations as a potential biomarker for detecting the prodromal AD stage.

Funder

Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México

Publisher

Hindawi Limited

Subject

Clinical Neurology,Neurology

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