Degradation and Transmission of Tau by Autophagic-Endolysosomal Networks and Potential Therapeutic Targets for Tauopathy

Abstract

Tauopathies are a class of neurodegenerative diseases, including Alzheimer's disease (AD), Frontotemporal Dementia (FTD), Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), and many others where microtubule-associated protein tau (MAPT or tau) is hyperphosphorylated and aggregated to form insoluble paired helical filaments (PHFs) and ultimately neurofibrillary tangles (NFTs). Autophagicendolysosomal networks (AELN) play important roles in tau clearance. Excessive soluble neurotoxic forms of tau and tau hyperphosphorylated at specific sites are cleared through the ubiquitin-proteasome system (UPS), Chaperon-mediated Autophagy (CMA), and endosomal microautophagy (e-MI). On the other hand, intra-neuronal insoluble tau aggregates are often degraded within lysosomes by macroautophagy. AELN defects have been observed in AD, FTD, CBD, and PSP, and lysosomal dysfunction was shown to promote the cleavage and neurotoxicity of tau. Moreover, several AD risk genes (e.g., PICALM, GRN, and BIN1) have been associated with dysregulation of AELN in the late-onset sporadic AD. Conversely, tau dissociation from microtubules interferes with retrograde transport of autophagosomes to lysosomes, and that tau fragments can also lead to lysosomal dysfunction. Recent studies suggest that tau is not merely an intraneuronal protein, but it can be released to brain parenchyma via extracellular vesicles, like exosomes and ectosomes, and thus spread between neurons. Extracellular tau can also be taken up by microglial cells and astrocytes, either being degraded through AELN or propagated via exosomes. This article reviews the complex roles of AELN in the degradation and transmission of tau, potential diagnostic/therapeutic targets and strategies based on AELN-mediated tau clearance and propagation, and the current state of drug development targeting AELN and tau against tauopathies.

Tau Oligomers Neurotoxicity

“…Autophagy can be divided into chaperone-mediated autophagy (CMA), endosomal microautophagy (e-MI), and macroautophagy [162]. Macroautophagy is the major cellular mechanism responsible for removing protein aggregates, such as insoluble tau aggregates [163], long-lived proteins, damaged organelles, and pathogens, whereas CMA [164] and e-MI [165] may degrade soluble neurotoxic forms of tau.…”

A brain proteomic signature of incipient Alzheimer’s disease in youngAPOEε4 carriers identifies novel drug targets

“…Recent evidence also suggests that LGALS8-mediated autophagy is important in preventing the entry of tau seeds into the cytosol and their subsequent aggregation ( 41 ). Our immunohistochemical studies demonstrate that LGALS8 is localized within neuronal lysosomes where it may play a role in autophagic degradation of intraneuronal tau ( 42 ). Our finding that dual-specificity phosphatase 3 (DUSP3), also known as VH1-related phosphatase (VHR), is localized within postsynaptic processes of both excitatory and inhibitory neurons is also consistent with its proposed role in countering excitotoxicity-induced neuronal death and Aβ accumulation ( 43 ).…”

Numb reduces Tau levels and prevents neurodegeneration in mouse models of tauopathy in an isoform-specific manner

“…While elucidating the precise molecular mechanisms by which Numb controls Tau levels will require further investigation, our findings indicate that Numb-72 promotes the release of native Tau monomers into the extracellular space. Several studies have shown that Tau is not only an intraneuronal protein, but can also be released in the extracellular space via exosomes and ectosomes (72,73,90,91). Although the release of Tau oligomers was reported to contribute to spreading of the pathology, physiological Tau can also be secreted by neurons through exosomes (92)(93)(94), which is thought to serve as a clearance mechanism to prevent pathological Tau formation (73).…”

“…S5D, F). Finally, we wondered whether Numb might promote the extracellular release of Tau, which is known to help balance intracellular levels in physiological and pathological conditions (72,73). We transfected GFP or Numb-72 in a Tau-expressing stable cell line and measured the levels of total Tau and oligomeric Tau in the culture medium 24 hours later by DotBlot assays.…”