Consequences of Hyperphosphorylated Tau in the Locus Coeruleus on Behavior and Cognition in a Rat Model of Alzheimer’s Disease

Article type: Research Article

Authors: Kelberman, Michael A.^{a; b; 1} | Anderson, Claire R.^{a; 1} | Chlan, Eli^{b; c} | Rorabaugh, Jacki M.^a | McCann, Katharine E.^a | Weinshenker, David^{a; *}

Affiliations: [a] Department of Human Genetics, Emory University, Atlanta, GA, USA | [b] Neuroscience Program, Laney Graduate School, Emory University, Atlanta, GA, USA | [c] Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA

Correspondence: [*] Correspondence to: David Weinshenker, 615 Michael St., Whitehead 301, Atlanta, GA 30322, USA. Tel.: +1 404 727 3106; E-mail: dweinsh@emory.edu.

Note: [1] These authors contributed equally to this work.

Abstract: Background:The locus coeruleus (LC) is one of the earliest brain regions to accumulate hyperphosphorylated tau, but a lack of animal models that recapitulate this pathology has hampered our understanding of its contributions to Alzheimer’s disease (AD) pathophysiology. Objective:We previously reported that TgF344-AD rats, which overexpress mutant human amyloid precursor protein and presenilin-1, accumulate early endogenous hyperphosphorylated tau in the LC. Here, we used TgF344-AD rats and a wild-type (WT) human tau virus to interrogate the effects of endogenous hyperphosphorylated rat tau and human tau in the LC on AD-related neuropathology and behavior. Methods:Two-month-old TgF344-AD and WT rats received bilateral LC infusions of full-length WT human tau or mCherry control virus driven by the noradrenergic-specific PRSx8 promoter. Rats were subsequently assessed at 6 and 12 months for arousal (sleep latency), anxiety-like behavior (open field, elevated plus maze, novelty-suppressed feeding), passive coping (forced swim task), and learning and memory (Morris water maze and fear conditioning). Hippocampal microglia, astrocyte, and AD pathology were evaluated using immunohistochemistry. Results:In general, the effects of age were more pronounced than genotype or treatment; older rats displayed greater hippocampal pathology, took longer to fall asleep, had reduced locomotor activity, floated more, and had impaired cognition compared to younger animals. TgF344-AD rats showed increased anxiety-like behavior and impaired learning and memory. The tau virus had negligible influence on most measures. Conclusion:Effects of hyperphosphorylated tau on AD-like neuropathology and behavioral symptoms were subtle. Further investigation of different forms of tau is warranted.

Keywords: Alzheimer’s disease, behavior, cognition, locus coeruleus, rat, tau, transgenic

DOI: 10.3233/JAD-215546

Journal: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1037-1059, 2022