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

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.

The Effects of CSF Neurogranin and APOE ε4 on Cognition and Neuropathology in Mild Cognitive Impairment and Alzheimer’s Disease

“…In terms of diagnostic accuracy, the different performance of CSF Ng on MCI ε4− and MCI ε4+ may be due to the fact that less MCI ε4− subjects would progress to AD dementia, while more MCI ε4+ subjects would progress to AD dementia. It is well known that tau protein is mainly distributed in the soma and axons of neurons ( Mandelkow, 1999 ; Wang and Mandelkow, 2016 ; Mondragón-Rodríguez et al, 2020 ). However, recent evidence suggested that tau is also a dendritic protein ( Mondragón-Rodríguez et al, 2012a , b , 2020 ; Regan and Piers, 2015 ).…”

“…It is well known that tau protein is mainly distributed in the soma and axons of neurons ( Mandelkow, 1999 ; Wang and Mandelkow, 2016 ; Mondragón-Rodríguez et al, 2020 ). However, recent evidence suggested that tau is also a dendritic protein ( Mondragón-Rodríguez et al, 2012a , b , 2020 ; Regan and Piers, 2015 ). Specifically, under physiological conditions, endogenous tau is located at the postsynaptic of neurons ( Mondragón-Rodríguez et al, 2012b , 2020 ).…”

“…However, recent evidence suggested that tau is also a dendritic protein ( Mondragón-Rodríguez et al, 2012a , b , 2020 ; Regan and Piers, 2015 ). Specifically, under physiological conditions, endogenous tau is located at the postsynaptic of neurons ( Mondragón-Rodríguez et al, 2012b , 2020 ). This raises an important question: What is the role of tau protein in postsynapses ( Mondragón-Rodríguez et al, 2020 )?…”

“…Specifically, under physiological conditions, endogenous tau is located at the postsynaptic of neurons ( Mondragón-Rodríguez et al, 2012b , 2020 ). This raises an important question: What is the role of tau protein in postsynapses ( Mondragón-Rodríguez et al, 2020 )? According to recent data, dendritic tau seems to regulate the plastic mechanisms related to memory storage ( Mondragón-Rodríguez et al, 2012b , 2020 ; Regan and Piers, 2015 ; Ittner et al, 2016 ).…”

“…This raises an important question: What is the role of tau protein in postsynapses ( Mondragón-Rodríguez et al, 2020 )? According to recent data, dendritic tau seems to regulate the plastic mechanisms related to memory storage ( Mondragón-Rodríguez et al, 2012b , 2020 ; Regan and Piers, 2015 ; Ittner et al, 2016 ). At the physiological and molecular levels, lasting changes in synaptic plasticity are considered to be cell-related factors for memory storage.…”