Equilibrative nucleoside transporter 1 inhibition rescues energy dysfunction and pathology in a model of tauopathy

Autor: Ya Gin Chang, Luc Buée, Kuo Chen Wu, Ching Pang Chang, Fang Yi Chou, Vincent Huin, Lee-Way Jin, Sin-Jhong Cheng, David Blum, Yung-Feng Liao, Pei Yun Chuang, Thi Ngoc Anh Nguyen, Hui Mei Chen, Chun-Jung Lin, Yijuang Chern, Kevin Carvalho
Přispěvatelé: Academia Sinica, National Taiwan University [Taiwan] (NTU), University of California [Davis] (UC Davis), University of California (UC), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Excellence Laboratory LabEx DISTALZ, ANR-18-CE16-0008,ADORASTrAU,Contribution des astrocytes aux troubles cognitifs induits par la protéine Tau neuronale dans la maladie d'Alzheimer(2018), BUEE, Luc, University of California, Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC))
Jazyk: angličtina
Rok vydání: 2021
Předmět:
AMPK
Aging
Neurology
Adenosine
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
Disease
Neurodegenerative
Equilibrative nucleoside transporter 1
Alzheimer's Disease
Mice
0302 clinical medicine
2.1 Biological and endogenous factors
Cognitive decline
Aetiology
Alzheimer's Disease Related Dementias (ADRD)
0303 health sciences
biology
Neurodegeneration
Brain
3. Good health
Frontotemporal Dementia (FTD)
Tauopathy
Tauopathies
Neurological
Alzheimer’s disease
ENT1
medicine.drug
medicine.medical_specialty
Clinical Sciences
Pathology and Forensic Medicine
Equilibrative Nucleoside Transporter 1
03 medical and health sciences
Cellular and Molecular Neuroscience
medicine
Acquired Cognitive Impairment
Animals
Humans
RC346-429
030304 developmental biology
business.industry
Animal
Research
Neurosciences
[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD)
medicine.disease
Brain Disorders
Disease Models
Animal
Disease Models
biology.protein
Dementia
Neurology (clinical)
Biochemistry and Cell Biology
Neurology. Diseases of the nervous system
business
Neuroscience
030217 neurology & neurosurgery
Zdroj: Acta Neuropathologica Communications
Acta Neuropathologica Communications, 2021, 9 (1), pp.112. ⟨10.1186/s40478-021-01213-7⟩
Acta Neuropathologica Communications, Vol 9, Iss 1, Pp 1-18 (2021)
Acta Neuropathologica Communications, BioMed Central part of Springer Science, 2021, 9 (1), pp.112. ⟨10.1186/s40478-021-01213-7⟩
Acta neuropathologica communications, vol 9, iss 1
ISSN: 2051-5960
DOI: 10.1186/s40478-021-01213-7⟩
Popis: Tau pathology is instrumental in the gradual loss of neuronal functions and cognitive decline in tauopathies, including Alzheimer’s disease (AD). Earlier reports showed that adenosine metabolism is abnormal in the brain of AD patients while consequences remained ill-defined. Herein, we aimed at investigating whether manipulation of adenosine tone would impact Tau pathology, associated molecular alterations and subsequent neurodegeneration. We demonstrated that treatment with an inhibitor (J4) of equilibrative nucleoside transporter 1 (ENT1) exerted beneficial effects in a mouse model of Tauopathy. Treatment with J4 not only reduced Tau hyperphosphorylation but also rescued memory deficits, mitochondrial dysfunction, synaptic loss, and abnormal expression of immune-related gene signatures. These beneficial effects were particularly ascribed to the ability of J4 to suppress the overactivation of AMPK (an energy reduction sensor), suggesting that normalization of energy dysfunction mitigates neuronal dysfunctions in Tauopathy. Collectively, these data highlight that targeting adenosine metabolism is a novel strategy for tauopathies. Supplementary Information The online version contains supplementary material available at 10.1186/s40478-021-01213-7.
Databáze: OpenAIRE
Externí odkaz: