Lysosomal TPCN (two pore segment channel) inhibition ameliorates beta-amyloid pathology and mitigates memory impairment in Alzheimer disease

Benjamin Chun-Kit Tong; Aston Jiaxi Wu; Alexis Shiying Huang; Rui Dong; Sandeep Malampati; Ashok Iyaswamy; Senthilkumar Krishnamoorthi; Sravan Gopalkrishnashetty Sreenivasmurthy; Zhou Zhu; Chengfu Su; Jia Liu; Juxian Song; Jia-Hong Lu; Jieqiong Tan; Weidong Pan; Min Li; King-Ho Cheung

doi:10.1080/15548627.2021.1945220

Lysosomal TPCN (two pore segment channel) inhibition ameliorates beta-amyloid pathology and mitigates memory impairment in Alzheimer disease

Autophagy. 2022 Mar;18(3):624-642. doi: 10.1080/15548627.2021.1945220. Epub 2021 Jul 27.

Authors

Benjamin Chun-Kit Tong¹, Aston Jiaxi Wu¹, Alexis Shiying Huang¹, Rui Dong², Sandeep Malampati¹, Ashok Iyaswamy¹, Senthilkumar Krishnamoorthi¹, Sravan Gopalkrishnashetty Sreenivasmurthy¹, Zhou Zhu¹, Chengfu Su¹, Jia Liu¹, Juxian Song³, Jia-Hong Lu⁴, Jieqiong Tan⁵, Weidong Pan⁶, Min Li¹, King-Ho Cheung¹

Affiliations

¹ School of Chinese Medicine and Mr. And Mrs. Ko Chi Ming Centre for Parkinson's Disease Research, Hong Kong Baptist University, Hong Kong, China.
² School of Biomedical Sciences, University of Hong Kong, Hong Kong, China.
³ Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China.
⁴ State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China.
⁵ Center for Medical Genetics and Hunan, Key Laboratory of Animal Model for Human Diseases, School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
⁶ Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang, China.

Abstract

Aβ: β-amyloid; AD: Alzheimer disease; AIF1/IBA1: allograft inflammatory factor 1; ALP: autophagy-lysosomal pathway; APP: amyloid beta precursor protein; ATP6V1B1/V-ATPase V1b1: ATPase H+ transporting V1 subunit B1; AVs: autophagy vacuoles; BAF: bafilomycin A₁; CFC: contextual/cued fear conditioning assay; CHX: Ca²⁺/H⁺ exchanger; CTF-β: carboxy-terminal fragment derived from β-secretase; CTSD: cathepsin D; fAD: familial Alzheimer disease; GFAP: glial fibrillary acidic protein; LAMP1: lysosomal associated membrane protein 1; LTP: long-term potentiation; MCOLN1/TRPML1: mucolipin 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPT: microtubule associated protein tau; MWM: Morris water maze; NFT: neurofibrillary tangles; PFC: prefrontal cortex; PSEN1: presenilin 1; SQSTM1/p62: sequestosome 1; TBS: theta burst stimulation; TEM: transmission electronic microscopy; TPCN2/TPC2: two pore segment channel 2; WT: wild-type; V-ATPase: vacuolar type H⁺-ATPase.

Keywords: Alzheimer disease; autophagy-lysosomal pathway; calcium ion; presenilin-1; two pore segment channel 2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphatases / metabolism
Alzheimer Disease* / pathology
Amyloid beta-Peptides / metabolism
Autophagy / physiology
Humans
Lysosomes / metabolism
Memory Disorders / metabolism
Vacuolar Proton-Translocating ATPases* / metabolism

Substances

ATP6V1B1 protein, human
Amyloid beta-Peptides
Adenosine Triphosphatases
Vacuolar Proton-Translocating ATPases

Grants and funding

This work was supported by the Hong Kong Baptist University [HKBU RC-EMF02/17]; Guangdong Natural Science Foundation [2019A1515011756]; Research Grants Council, University Grants Committee (HK) [HKBU/17104514, HKBU/12100321, HKBU/12101417, HKBU/12100618]; Health and Medical Research Fund (HK) [15163421, 15163481, 17182541, 17182551 and 17182561].