Macroautophagy/autophagy deficit induces intracellular MAPT/tau accumulation, the hallmark pathology in
Alzheimer disease (AD) and other
tauopathies; however, the reverse role of MAPT accumulation in autophagy and neurodegeneration is not clear. Here, we found that overexpression of human wild-type full-length MAPT, which models MAPT pathologies as seen in sporadic AD patients, induced autophagy deficits via repression of autophagosome-lysosome fusion leading to significantly increased LC3 (
microtubule-associated protein 1 light chain 3)-II and SQSTM1/p62 (
sequestosome 1) protein levels with autophagosome accumulation. At the molecular level, intracellular MAPT aggregation inhibited expression of IST1 (IST1 factor associated with
ESCRT-III), a positive modulator for the formation of ESCRT (the
Endosomal Sorting Complex Required for Transport) complex that is required for autophagosome-lysosome fusion. Upregulating IST1 in human MAPT transgenic mice attenuated autophagy deficit with reduced MAPT aggregation and ameliorated synaptic plasticity and cognitive functions, while downregulating IST1 per se induced autophagy deficit with impaired synapse and cognitive function in naïve mice. IST1 can facilitate association of CHMP2B (charged multivesicular body
protein 2B) and CHMP4B/SNF7-2 to form
ESCRT-III complex, while lack of IST1 impeded the complex formation. Finally, we demonstrate that MAPT accumulation suppresses IST1 transcription with the mechanisms involving the ANP32A-regulated mask of
histone acetylation. Our findings suggest that the AD-like MAPT accumulation can repress autophagosome-lysosome fusion by deregulating ANP32A-INHAT-IST1-ESCRT-III pathway, which also reveals a vicious cycle of MAPT accumulation and autophagy deficit in the chronic course of AD neurodegeneration.Abbreviations: AAV: adeno-associated virus; Aβ: β-
amyloid; aCSF: artificial cerebrospinal fluid; AD:
Alzheimer disease; ANP32A: acidic nuclear
phosphoprotein 32 family member A; ATG: autophagy related; AVs: autophagic vacuoles; CEBPB:
CCAAT enhancer binding protein beta; CHMP: charged multivesicular body
protein; DMEM: Dulbecco's modified eagle's medium; EBSS: Earle's balanced
salt solution; EGFR:
epidermal growth factor receptor; ESCRT:
endosomal sorting complex required for transport; fEPSPs: field excitatory postsynaptic potentials; GAPDH:
glyceraldehyde-3-phosphate dehydrogenase; GSK3B:
glycogen synthase kinase 3 beta; HAT:
histone acetyl
transferase; HDAC:
histone deacetylase; INHAT: inhibitor of
histone acetyl
transferase; IST1: IST1 factor associated with
ESCRT-III; LAMP2:
lysosomal associated membrane protein 2; LTP: long-term potentiation; MAP1LC3:
microtubule associated protein 1 light chain 3; MAPT/tau:
microtubule associated protein tau; MVB: multivesicular bodies; MWM: Morris water maze; PBS:
phosphate-buffered
saline solution; RAB7: member RAS oncogene family;
SNAREs:
soluble N-ethylmaleimide-sensitive factor attachment protein receptors; SQSTM1/p62: sequestosome 1.