Increased neuronal activity in motor cortex reveals prominent calcium dyshomeostasis in tauopathy mice

NEUROBIOLOGY OF DISEASE

卷:147

Article

Wu, Qian^1,2  Bai, Yang^1,2,3  Li, Wei^1,2,3  Congdon, Erin E.^1,2  Liu, Wenke⁴  Lin, Yan^1,2  Ji, Changyi^1,2  Gan, Wen-Biao^1,2,3  Sigurdsson, Einar M.^1,2,4 

[1] NYU, Dept Neurosci & Physiol, Grossman Sch Med, Sci Bldg,435 East 30th St, New York, NY 10016 USA

[2] NYU, Neurosci Inst, Grossman Sch Med, Sci Bldg,435 East 30th St, New York, NY 10016 USA

[3] NYU, Skirball Inst, Grossman Sch Med, 550 First Ave, New York, NY 10016 USA

[4] NYU, Dept Psychiat, Grossman Sch Med, 550 First Ave, New York, NY 10016 USA

关键词: Frontotemporal dementia;    Tau;    Antibody;    Ca2+;    Two-photon imaging;    Mice;   

DOI  :  10.1016/j.nbd.2020.105165

来源: Elsevier

【 摘 要 】

Perturbed neuronal Ca2+ homeostasis is implicated in Alzheimer's disease, which has primarily been demonstrated in mice with amyloid-beta deposits but to a lesser and more variable extent in tauopathy models. In this study, we injected AAV to express Ca2+ indicator in layer II/III motor cortex neurons and measured neuronal Ca2+ activity by two photon imaging in awake transgenic JNPL3 tauopathy and wild-type mice. Various biochemical measurements were conducted in postmortem mouse brains for mechanistic insight and a group of animals received two intravenous injections of a tau monoclonal antibody spaced by four days to test whether the Ca2+ dyshomeostasis was related to pathological tau protein. Under running conditions, we found abnormal neuronal Ca2+ activity in tauopathy mice compared to age-matched wild-type mice with higher frequency of Ca2+ transients, lower amplitude of peak Ca2+ transients and lower total Ca2+ activity in layer II/III motor cortex neurons. While at resting conditions, only Ca2+ frequency was increased. Brain levels of soluble pathological tau correlated better than insoluble tau levels with the degree of Ca2+ dysfunction in tauopathy mice. Furthermore, tau monoclonal antibody 4E6 partially rescued Ca2+ activity abnormalities in tauopathy mice after two intravenous injections and decreased soluble pathological tau protein within the brain. This correlation and antibody effects strongly suggest that the neuronal Ca2+ dyshomeostasis is causally linked to pathological tau protein. These findings also reveal more pronounced neuronal Ca2+ dysregulation in tauopathy mice than previously reported by two-photon imaging that can be partially corrected with an acute tau antibody treatment.