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Cell Physiol Biochem. 2017 Oct 31;43(6):2446-2456. doi: 10.1159/000484449. [Epub ahead of print]

TRPML1 Participates in the Progression of Alzheimer's Disease by Regulating the PPARγ/AMPK/Mtor Signalling Pathway.

Author information

1
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
2
Department of Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
3
Department of Legal Medicine, The College of Basic Medical Sciences of Zhengzhou University, Zhengzhou, China.

Abstract

BACKGROUND:

TRPML1 is reported to be involved in the pathogenesis of Alzheimer's disease (AD) by regulating autophagy; however, the underlying mechanism is not completely clear.

METHODS:

We developed an APP/PS1 transgenic animal model that presents with AD. TRPML1 was also overexpressed in these mice. Protein expression levels were determined by Western blot. Morris water maze (MWM) and recognition tasks were performed to characterize cognitive ability. TUNEL assays were analysed for the detection of neuronal apoptosis. Primary neurons were isolated and treated with the vehicle, Aβ1-42 or Aβ1-42 + mTOR activator, as well as infected with the recombinant adenovirus TRPML1 overexpression vector in vitro. Cell viability was measured by the MTS assay, and lysosomal Ca2+ was also measured.

RESULTS:

In the APP/PS1 transgenic mice, TRPML1 was downregulated, the PPARγ/AMPK signalling pathway was activated, the mTOR/S6K signalling pathway was suppressed, and autophagic lysosome reformation (ALR)-related proteins were upregulated. TRPML1 overexpression or treatment with PPARγ and AMPK inhibitors or an mTOR activator reduced the expression levels of ALR-related proteins, rescued the memory and recognition impairments and attenuated neuronal apoptosis in mice with the APP/PS1 transgenes. In vitro experiments showed that TRPML1 overexpression or treatment with the mTOR activator propranolol attenuated the Aβ1-42-suppressed cell viability and the Aβ1-42-decreased lysosomal [Ca2+] ion concentration in primary neurons. TRPML1 overexpression or treatment with the mTOR activator propranolol also attenuated the Aβ1-42-inhibited mTOR/S6K signalling pathway and the Aβ1-42-induced ALR-related protein expression levels.

CONCLUSION:

TRPML1 is involved in the pathogenesis of AD by regulating autophagy at least in part through the PPARγ/AMPK/mTOR signallingpathway.

KEYWORDS:

Alzheimer’s disease; PPARγ/AMPK/ mTOR/S6K signalling pathway; Trpml1

PMID:
29131026
DOI:
10.1159/000484449
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