Physiological and Pathophysiological Implications of Synaptic Tau

Abstract

Tauopathies encompass a broad range of neurodegenerative diseases featuring extensive neuronal death and cognitive decline. However, research over the past thirty years has failed to significantly advance our understanding of how tau causes dementia, limiting the design of rational therapeutics. It has become evident that we need to expand our understanding of tau in physiology, in order to delineate how tau may contribute to pathology. This review will discuss recent evidence that has uncovered a novel aspect of tau function, based on its previously uncharacterised localisation to the synapse. Here, multiple streams of evidence support a critical role for synaptic tau in the regulation of synapse physiology. In particular, long-term depression, a form of synaptic weakening, is dependent on the presence of tau in hippocampal neurons. The regulation of tau by specific phosphorylation events downstream of GSK-3β activation appears to be integral to this signalling role. We will also describe how the regulation of synapse physiology by tau and its phosphorylation may inform our understanding of tauopathies and co-morbid diseases. This work should provide a platform for future tau biology research in addition to therapeutic design.

Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease

“…The etiological relationships between neuronal accumulation of primary neurotoxic proteins and decreases in synaptic proteins that lead to early synaptic dysfunction are now being unraveled definitively. Recent evidence from several lines of research has shown intensive localization of tau with a distinctive pattern of phosphorylation at neuronal synapses in AD and several other pathophysiologic tauopathies (36). The capacity of synaptic P‐tau to alter synaptic physiology is particularly evident in long‐term depression of synaptic signaling in hippocampal neurons.…”

Synaptic distributions of pS214‐tau in rhesus monkey prefrontal cortex are associated with spine density, but not with cognitive decline

“…Our data cannot reveal the precise underlying mechanism by which pS214‐tau might play a physiological role within monkey dlPFC synapses, but there are several possibilities. For instance, tau has recently been proposed as a potential mediator of actin and microtubule cytoskeletal network organization; microtubule‐dependent transport of critical cargoes such as mitochondria; and, neuronal excitability, including glutamatergic synaptic transmission (Regan, Whitcomb, & Cho, ; Y. Wang & Mandelkow, ). The latter may partly occur through complex interactions between tau, and the PSD95‐GluN2B‐Fyn complex (L. M. Ittner et al, ; Lau et al, ; Mondragon‐Rodriguez et al, ; Roberson et al, ).…”

“…Impaired trafficking of tau to the synapse with aging is one possible explanation for this observation, though this has yet to be tested empirically in our model. Indeed, axonal transport is known to decrease with age, and decreased axonal transport has been invoked as a potential mechanism of neurodegeneration for multiple neurodegenerative disorders, including AD (Ballatore, Lee, & Trojanowski, 2007;Milde, Adalbert, Elaman, & Coleman, 2015;Millecamps & Julien, 2013;Regan et al, 2016). Tau is transported through the axon, and thus, presumably to postsynaptic locations, including spines, as well.…”

Palmitoylation in Alzheimer⿿s disease and other neurodegenerative diseases

“…By adopting the view of synaptic tau in AD [183], given that LTD-inducing NMDA receptor stimulation led to tau phosphorylation, which regulates the interaction with Fyn [184], and that tau phosphorylation is required for LTD [184,185], which could be a cellular basis for aberrant synaptic weakening and loss observed in AD [183], and that palmitoylation of the protein interacting with C-kinase (PICK1), a GluA2-interacting protein [186] is critical for cerebellar LTD induction [187], investigating palmitoylation of tau-and/or glutamate receptorregulating factors will provide insights into synaptic roles of palmitoylation particularly in AD.…”