Journal
BEHAVIOURAL BRAIN RESEARCH
Volume 216, Issue 1, Pages 332-340Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbr.2010.08.013
Keywords
Alzheimer's disease; Hippocampal formation; Learned alternation; P301L; Retrohippocampal area; Tauopathy; Y-maze
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Funding
- National Institutes of Health [MH060608, NIA P10485, NS048450]
- Howard Hughes Medical Institute [52005120]
- U.S. Department of Veterans Affairs
- NATIONAL INSTITUTE OF MENTAL HEALTH [R15MH060608] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS048450] Funding Source: NIH RePORTER
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Entorhinal cortex neuropathology begins very early in Alzheimer's disease (AD), a disorder characterized by severe memory disruption. Indeed, loss of entorhinal volume is predictive of AD and two of the hallmark neuroanatomical markers of AD, amyloid plaques and neurofibrillary tangles (NFTs), are particularly prevalent in the entorhinal area of AD-afflicted brains. Gene transfer techniques were used to create a model neurofibrillary tauopathy by injecting a recombinant adeno-associated viral vector with a mutated human tau gene (P301L) into the entorhinal cortex of adult rats. The objective of the present investigation was to determine whether adult onset, spatially restricted tauopathy could be sufficient to reproduce progressive deficits in mnemonic function. Spatial memory on a Y-maze was tested for approximately 3 months post-surgery. Upon completion of behavioral testing the brains were assessed for expression of human tau and evidence of tauopathy. Rats injected with the tau vector became persistently impaired on the task after about 6 weeks of postoperative testing, whereas the control rats injected with a green fluorescent protein vector performed at criterion levels during that period. Histological analysis confirmed the presence of hyperphosphorylated tau and NFTs in the entorhinal cortex and neighboring retrohippocampal areas as well as limited synaptic degeneration of the perforant path. Thus, highly restricted vector-induced tauopathy in retrohippocampal areas is sufficient for producing progressive impairment in mnemonic ability in rats, successfully mimicking a key aspect of tauopathies such as AD. (C) 2010 Elsevier B.V. All rights reserved.
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