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.
Highlights
Alzheimer’s disease (AD) is a public health problem for our aging societies and is histopathologically defined by extracellular amyloid-beta (Aβ) deposits and intracellular hyperphosphorylated Tau deposits [1,2,3,4,5,6,7]
The following is a summary of this evidence: (1) Tau phosphorylation at specific sites appears during early stages of disease progression in the brain tissue from AD, Parkinson’s disease, Down syndrome, and frontotemporal dementia cases [2, 5,6,7, 98, 99]
(4) Endogenous pTau near microtubule domain (MD) sites is physiologically located at postsynaptic sites where it interacts with the PSD95NMDAr complex [13, 14, 29]
Summary
Alzheimer’s disease (AD) is a public health problem for our aging societies and is histopathologically defined by extracellular amyloid-beta (Aβ) deposits and intracellular hyperphosphorylated Tau (pTau) deposits [1,2,3,4,5,6,7]. Intensive research focusing on the pathological role of pTau has strongly nurtured the use of pTau as a therapeutic target [12, 13] These therapeutic approaches have been restricted to a reduction of Tau levels and lowering activity of kinases that phosphorylate Tau [12, 13]. As for Neural Plasticity the numerous AD therapies that have aimed towards Aβ, we predict that the Tau-based strategy will render mild outcomes To justify this hypothesis, it is critically important to discuss the pathological and the physiological functions of pTau [13, 14], namely, its recently described synaptic functions [13,14,15]. This review appraises the available evidence on neural network dysfunction in preclinical and confirmed AD, identifies research gaps on current AD hypotheses, and points towards new research directions to understand and treat this disease
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