| 研究実績の概要 |
The aim of this project is to demonstrate that enhancement of autophagy/lysosomal
function through activation of Transcription Factor EB (TFEB) will increase the degradation of intracellular forms of disease-related proteins such as phosphorylated alpha synuclein (p-syn) and tau (p-tau). We examined the expression of progranulin (PGRN) and prosaposin (PSAP), regulators of lysosomal function, in the brain of Alzheiemer's disease (AD), and found the association of PGRN and PSAP with amyloid plaques in non-demented aged control and AD brains. Next, we investigated the possible involvement of PGRN and PSAP in tangle formation using human brain tissue sections of non-demented aged control subjects and AD cases, and compared with cases of fronto-temporal dementia (FTD) with granulin (GRN) mutations. The study revealed that decreased amounts of PGRN and PSAP proteins were detected in immature neurofibrillary tangles, while colocalization was still evident in adjacent neurons in all cases. Results suggest that neuronal loss of PGRN preceded loss of PSAP as tangles matured.The granulin mutation cases exhibited absence of PGRN in most neurons, while PSAP signal was preserved. We conclude that reduced levels of PGRN and PSAP and their interaction in neurons might predispose to accumulation of p-tau protein due to deficits in lysosomal activity.
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