Title: Interactions of Perirhinal Tau Pathology and Aging in Cognitive Dysfunction Abstract: Intracellular inclusions comprised of tau proteins are among the earliest pathological features of Alzheimer's disease (AD), the most common age-associated neurodegenerative condition. Data show that tau inclusions initially emerge in the transentorhinal subregion (area 35) of perirhinal cortex by the fourth decade of life, twenty years prior to the typical AD diagnosis. The immediate consequences of this early area 35 tau pathology on cognition and disease progression, however, remain poorly understood. The long-term goal of this research is to develop sensitive cognitive assays for humans that provide a reliable index of early AD pathology. The primary objective of the current proposal is to develop a preclinical model that recapitulates many features of early AD using AAV technology to drive pathological tau burden in area 35 of young and aged rats. The secondary goal of this proposal is to establish behavioral assays as a biomarker for early detection and tracking of disease pathology in patient populations. These goals will be attained by testing the hypothesis that aging exacerbates tau burden in area 35 and that progressive pathology in this brain region is associated with performance on sensory discrimination tasks that utilize perceptual gradients to test stimulus discrimination abilities. The rationale for this this work is that because Alzheimer's disease develops against the backdrop of an aging brain, it is critical to elucidate how aging and pathological tau interact to influence disease mechanisms and cognitive outcomes associated with disease progression. This work is innovative because viral vector technology will be used to model the specific anatomical features of early Alzheimer's disease in conjunction with state-of-the-art cognitive assays that are highly sensitive to detecting behavioral dysfunction associated with aging and disease. The significance of the proposed experiments will be to establish the foundation for developing new diagnostic tools for AD that can facilitate early intervention and more effectively evaluate the efficacy of novel therapeutics before widespread neurodegeneration occurs.
The proposed research is relevant to public health because it provides a new animal model of pre-clinical Alzheimer's disease as well as develop new behavioral assays for early detection. This will be achieved by using viral vector technology in aged rats to drive the expression of tau in the perirhinal cortex, the brain region that first shows neurofibrillary tangles in Alzheimer's disease, and then testing animals on behavioral tasks sensitive to dysfunction in this brain region. By understanding how tau and aging interact to affect behavior, it could be possible to promote the development of interventions that improve cognition in Alzheimer's disease and meet a mission of the NIA to advance our understanding of age-related cognitive decline.
