Abstract
Cholinergic impairments and tau accumulation are hallmark pathologies in sporadic Alzheimer’s disease (AD), however, the intrinsic link between tau accumulation and cholinergic deficits is missing. Here, we found that overexpression of human wild-type full-length tau (termed hTau) induced a significant reduction of α4 subunit of nicotinic acetylcholine receptors (nAChRs) with an increased cleavage of the receptor producing a ~55kDa fragment in primary hippocampal neurons and in the rat brains, meanwhile, the α4 nAChR currents decreased. Further studies demonstrated that calpains, including calpain-1 and calpain-2, were remarkably activated with no change of caspase-3, while simultaneous suppression of calpain-2 by selective calpain-2 inhibitor but not calpain-1 attenuated the hTau-induced degradation of α4 nAChR. Finally, we demonstrated that hTau accumulation increased the basal intracellular calcium level in primary hippocampal neurons. We conclude that the hTau accumulation inhibits nAChRs α4 by activating calpain-2. To our best knowledge, this is the first evidence showing that the intracellular accumulation of tau causes cholinergic impairments.
Highlights
Temporal cortex of Alzheimer’s disease (AD) patients[19]
AD is the most common neurodegenerative disease characterize by loss of cholinergic neurons, which begins in entorhinal cortex at early stage of the disease onset and later spreads to the limbic hippocampus and neocortex with reduced nAChR23,24
Previous studies show that the α4 nicotinic acetylcholine receptors (nAChRs) subunit was exclusively expressed in neurons, whereas α7 nAChR subunit was strongly expressed in neurons and astrocytes
Summary
Temporal cortex of AD patients[19]. Cholinergic degeneration in AD is correlated with decline of the cognitive functions[20]. To explore the role of tau accumulation in cholinergic impairments, we overexpressed human full length tau (hTau) in cultured hippocampus neurons and in rat brain hippocampus, and measured the expression level of nAChR α4 and the function. We found that overexpression of hTau induced degradation of nAChR α4 with activation of calpains, and simultaneous inhibition of calpain-2 but not calpain-1 arrested the hTau-induced degradation of nAChR α4
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