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Front Aging Neurosci. 2017 Jun 12;9:180. doi: 10.3389/fnagi.2017.00180. eCollection 2017.

The Impact of Aging on Brain Pituitary Adenylate Cyclase Activating Polypeptide, Pathology and Cognition in Mice and Rhesus Macaques.

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Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical CenterPhoenix, AZ, United States.
Department of Pathology and Laboratory Medicine Resident Program, Medical University of South CarolinaCharleston, SC, United States.
California National Primate Research Center, University of California, DavisDavis, CA, United States.
Evely F. McKnight Brain Institute, University of ArizonaTucson, AZ, United States.
Institute for Neurodegenerative Diseases, University of California, San FranciscoSan Francisco, CA, United States.
Civin Laboratory for Neuropathology, Banner Sun Health Research InstituteSun City, AZ, United States.
Division of Neural Systems, Memory and Aging, University of ArizonaTucson, AZ, United States.
Departments of Psychology, Neurology, and Neuroscience, University of ArizonaTucson, AZ, United States.
Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General HospitalTianjin, China.


Pituitary adenylate cyclase activating polypeptide (PACAP) is associated with Alzheimer's disease (AD), but its age-related effects are unknown. We chose the rhesus macaque due to its closeness to human anatomy and physiology. We examined four variables: aging, cognitive performance, amyloid plaques and PACAP. Delayed nonmatching-to-sample recognition memory scores declined with age and correlated with PACAP levels in the striatum, parietal and temporal lobes. Because amyloid plaques were the only AD pathology in the old rhesus macaque, we further studied human amyloid precursor protein (hAPP) transgenic mice. Aging was associated with decreased performance in the Morris Water Maze (MWM). In wild type (WT) C57BL/6 mice, the performance was decreased at age 24-26 month whereas in hAPP transgenic mice, it was decreased as early as 9-12 month. Neuritic plaques in adult hAPP mice clustered in hippocampus and adjacent cortical regions, but did not propagate further into the frontal cortex. Cerebral PACAP protein levels were reduced in hAPP mice compared to age-matched WT mice, but the genetic predisposition dominated cognitive decline. Taken together, these data suggest an association among PACAP levels, aging, cognitive function and amyloid load in nonhuman primates, with both similarities and differences from human AD brains. Our results suggest caution in choosing animal models and in extrapolating data to human AD studies.


Alzheimer’s disease; PACAP; aging; nonhuman primates

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