Abstract
Impaired clearance of Amyloid β (Aβ) by microglia in the brain may be associated with the senile plaque formation, a pathological hallmark relevant to Alzheimer's disease. Microglial cells in the brain are not able to efficiently degrade Aβ, suggesting that microglial lysosome impairment may occur. However, the mechanism of Aβ-induced impairment of microglia remains poorly understood. We observed the effects of Aβ on the trafficking of nuclear transcriptional factor EB (TFEB), a master regulator of lysosome biogenesis, and the expression of a downstream osteoporosis-associated transmembrane protein 1 (OSTM1), a vital molecule involved in lysosome acidification in primary microglial cells. Aβ1−42 but not Aβ42−1 resulted in a significant release of tumor necrosis factor-α in primary microglia, but the total cellular TFEB was not changed. Further, Aβ induced a dose-dependent reduction of the TFEB in the nucleus of primary microglial cells, coincident with the increase in the plasma, as revealed by Western blot and confocal microscopy. In addition, a dramatic decrease of OSTM1 expression was observed in the Aβ-challenged microglial cells, along with the intracellular pH steady state, indicating the inadequate lysosomal acidification. These data suggest that Aβ might result in a lysosomal dysfunction via inhibiting nuclear TFEB translocation in microglial cells.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative illness accounting for approximately 50–70% of late-onset dementia (Rademakers and Rovelet-Lecrux, 2009)
Most studies found that microglial cells were incapable of digesting engulfed fibrillar β-amyloid (fAβ), since the lysosomal acidification is inadequate for the digesting process, strongly suggesting the involvement of lysosomal dysfunction in the β-Amyloid and transcriptional factor EB (TFEB) in Microglia impaired fAβ degradation (Majumdar et al, 2007; Umeda et al, 2011)
Purified microglial cells were collected after treatment with Amyloid β (Aβ) and cell extracts were run on SDS-PAGE for immunoblotting to detect total TFEB level
Summary
Alzheimer’s disease (AD) is a neurodegenerative illness accounting for approximately 50–70% of late-onset dementia (Rademakers and Rovelet-Lecrux, 2009). Most studies found that microglial cells were incapable of digesting engulfed fAβ, since the lysosomal acidification is inadequate for the digesting process, strongly suggesting the involvement of lysosomal dysfunction in the β-Amyloid and TFEB in Microglia impaired fAβ degradation (Majumdar et al, 2007; Umeda et al, 2011) Evidences from both in vitro and in vivo showed that microglia could not effectively clear the fAβ in the brain, due to the lysosomal dysfunction (Hickman et al, 2008; Lee and Landreth, 2010; Perry et al, 2010). The mechanisms underlying the Aβ-induced lysosomal dysfunction remain unclear
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