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

Autor:	Kelberman MA; Department of Human Genetics, Emory University, Atlanta, GA, USA.; Neuroscience Program, Laney Graduate School, Emory University, Atlanta, GA, USA., Anderson CR; Department of Human Genetics, Emory University, Atlanta, GA, USA., Chlan E; Neuroscience Program, Laney Graduate School, Emory University, Atlanta, GA, USA.; Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA., Rorabaugh JM; Department of Human Genetics, Emory University, Atlanta, GA, USA., McCann KE; Department of Human Genetics, Emory University, Atlanta, GA, USA., Weinshenker D; Department of Human Genetics, Emory University, Atlanta, GA, USA.
Jazyk:	angličtina
Zdroj:	Journal of Alzheimer's disease : JAD [J Alzheimers Dis] 2022; Vol. 86 (3), pp. 1037-1059.
DOI:	10.3233/JAD-215546
Abstrakt:	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.
Databáze:	MEDLINE
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