期刊
JOURNAL OF ALZHEIMERS DISEASE
卷 86, 期 3, 页码 1037-+出版社
IOS PRESS
DOI: 10.3233/JAD-215546
关键词
Alzheimer's disease; behavior; cognition; locus coeruleus; rat; tau; transgenic
资金
- National Institute of Aging [AG062581, AG069502]
- National Institute of Neurological Disorders and Stroke [MS96050]
- Eli Lilly Innovation Fellowship Award
- Rodent Behavioral Core (RBC) - Emory University School of Medicine
- Emory Neuroscience NINDS Core Facilities [P30NS055077]
- Georgia Clinical & Translational Science Alliance of the National Institutes of Health [UL1TR002378]
- Viral Vector Core of the Emory Center for Neurodegenerative Disease Core Facilities
- Vector Core of the University of Pennsylvania
This study investigated the effects of hyperphosphorylated tau on AD-related neuropathology and behavior using TgF344-AD rats and WT rats as well as relevant viral models. The results showed that the effects of hyperphosphorylated tau on AD-like neuropathology and behavioral symptoms were subtle.
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 wildtype (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.
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