Learning Deficits Accompanied by Microglial Proliferation After the Long-Term Post-Injection of Alzheimer’s Disease Brain Extract in Mouse Brains

Article type: Research Article

Authors: Hayashi, Tetsuo^a | Shimonaka, Shotaro^{b; c} | Elahi, Montasir^{a; b} | Matsumoto, Shin-Ei^d | Ishiguro, Koichi^a | Takanashi, Masashi^a | Hattori, Nobutaka^{a; b} | Motoi, Yumiko^{a; b; *}

Affiliations: [a] Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan | [b] Department of Diagnosis, Prevention and Treatment of Dementia, Juntendo University School of Medicine, Tokyo, Japan | [c] Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo, Japan | [d] Department of Immunology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan

Correspondence: [*] Correspondence to: Yumiko Motoi, Department of Diagnosis, Prevention and Treatment of Dementia, Juntendo University School of Medicine, Tokyo 113-8421 Japan. Tel.: +81 3 3813 3111; Fax: +81 3 5800 0547; E-mail: motoi@juntendo.ac.jp.

Abstract: Background:Human tauopathy brain injections into the mouse brain induce the development of tau aggregates, which spread to functionally connected brain regions; however, the features of this neurotoxicity remain unclear. One reason may be short observational periods because previous studies mostly used mutated-tau transgenic mice and needed to complete the study before these mice developed neurofibrillary tangles. Objective:To examine whether long-term incubation of Alzheimer’s disease (AD) brain in the mouse brain cause functional decline. Methods:We herein used Tg601 mice, which overexpress wild-type human tau, and non-transgenic littermates (NTg) and injected an insoluble fraction of the AD brain into the unilateral hippocampus. Results:After a long-term (17–19 months) post-injection, mice exhibited learning deficits detected by the Barnes maze test. Aggregated tau pathology in the bilateral hippocampus was more prominent in Tg601 mice than in NTg mice. No significant changes were observed in the number of Neu-N positive cells or astrocytes in the hippocampus, whereas that of Iba-I-positive microglia increased after the AD brain injection. Conclusion:These results potentially implicate tau propagation in functional decline and indicate that long-term changes in non-mutated tau mice may reflect human pathological conditions.

Keywords: Microglia, neurodegeneration, propagation, tau protein, tauopathies

DOI: 10.3233/JAD-201002

Journal: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1701-1711, 2021