Atypical, non-standard functions of the microtubule associated Tau protein

Abstract

Since the discovery of the microtubule-associated protein Tau (MAPT) over 40 years ago, most studies have focused on Tau’s role in microtubule stability and regulation, as well as on the neuropathological consequences of Tau hyperphosphorylation and aggregation in Alzheimer’s disease (AD) brains. In recent years, however, research efforts identified new interaction partners and different sub-cellular localizations for Tau suggesting additional roles beyond its standard function as microtubule regulating protein. Moreover, despite the increasing research focus on AD over the last decades, Tau was only recently considered as a promising therapeutic target for the treatment and prevention of AD as well as for neurological pathologies beyond AD e.g. epilepsy, excitotoxicity, and environmental stress. This review will focus on atypical, non-standard roles of Tau on neuronal function and dysfunction in AD and other neurological pathologies providing novel insights about neuroplastic and neuropathological implications of Tau in both the central and the peripheral nervous system.

Endolysosomal degradation of Tau and its role in glucocorticoid-driven hippocampal malfunction

“…Tau accumulation and hyperphosphorylation is linked to synaptic atrophy, neuronal dysfunction, and cognitive deficits 4,5 , and triggers these events by disrupting axonal trafficking 6 , promoting GluN2B-related excitotoxicity 2,7 , and suppressing nuclear CREB-mediated synthesis of synapse-and memory-related proteins 5 , among other effects. Furthermore, emerging studies support a crucial role for Tau in diverse brain pathologies (for review, see 8 ) including prolonged exposure to stressful conditions, a known risk factor for AD and major depressive disorder 9 . In particular, recent studies demonstrate that exposure to chronic environmental stress or the major stress hormones, glucocorticoids (GC), triggers the accumulation of Tau and its synaptic missorting, precipitating dendritic atrophy and synaptic dysfunction in a Tau-dependent manner [10][11][12][13][14] .…”

“…These studies indicate that the Rab35/ESCRT pathway is essential for Tau clearance and part of the mechanism through which GC precipitate brain pathology. brain pathologies (for review, see (Sotiropoulos, Galas et al, 2017)) including prolonged exposure to stressful conditions, a known risk factor for AD and major depressive disorder (Vyas, Rodrigues et al, 2016). In particular, recent studies demonstrate that exposure to chronic environmental stress or the major stress hormones, glucocorticoids (GC), triggers the accumulation of Tau and its synaptic missorting, precipitating dendritic atrophy and synaptic dysfunction in a Tau-dependent…”

Mutual Relationship between Tau and Central Insulin Signalling: Consequences for AD and Tauopathies?

“…It is however now considered that, beyond microtubules, Tau exerts much larger neuronal functions, notably at the level of synapses and nuclei [73-75]. Tau is also physiologically released by neurons [76] even if the natural function of extracellular Tau remains to be uncovered [77]. …”

Central nervous system lymphatic unit, immunity, and epilepsy: Is there a link?

“…57,58 Results were corroborated by using experimental models of epilepsy 59 or of TBI associated with the development of seizures. 60,61 pTau has been implicated in the regulation of neuronal network synchronization 62,63 and in neuroplasticity changes 64,65 resulting in hyperexcitability. 63 In a murine model of Alzheimer disease, the reduction of pTau levels corresponded to decreased electroencephalographic seizures.…”