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Amelioration of Memory Deficits in a Transgenic Mouse Model of Alzheimer’s Disease by Manipulation of the Histone Acetyltransferase p300/CBP Associated Factor (PCAF)

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Title: Amelioration of Memory Deficits in a Transgenic Mouse Model of Alzheimer’s Disease by Manipulation of the Histone Acetyltransferase p300/CBP Associated Factor (PCAF)
Author: Creighton, Samantha
Department: Department of Psychology
Program: Psychology
Advisor: Winters, Boyer
Abstract: Acetylation of histone and non-histone proteins by histone acetyltransferases (HATs) supports many mnemonic processes. As there is growing evidence that dysregulation of acetylation plays a role in cognitive deficits and neuropathology in Alzheimer’s disease (AD), increasing HAT activity has emerged as a promising therapeutic strategy. However, acetylation patterns in AD are likely multifarious and memory deficits may not always be ameliorated by simply activating HATs. Indeed, the HAT, PCAF, may function atypically in AD. While PCAF activation enhances memory in normal rodents, in Ab-treated rats, PCAF inhibition or knockout attenuates AD-like cognitive deficits, suggesting that PCAF activity may actually be detrimental. By longitudinally characterizing object (object recognition; OR) and spatial (object location; OL) memory deficits at 3, 6, 9, and 12- months-of-age, we show that male and female triple transgenic mice (3xTG) develop progressive cognitive impairments. Acute PCAF activation and inhibition remediated these impairments in an age-related bidirectional manner. At 3 and 6 months of age, prior to the development of OR deficits, the PCAF activator, SPV106, enhanced short- (5min) and long-term (3h) OR, whereas the PCAF inhibitor, embelin, impaired. At 9 months of age, when OR impairment was first observed, SPV106 ameliorated the long-term OR deficit. At 12 months of age, however, SPV106 induced a short-term OR impairment, while embelin ameliorated the long-term OR deficit. A similar, albeit accelerated, pattern of results was observed for spatial memory using the object location task (OL). OL impairments were first observed at 3 months of age. At both 3 and 6 months of age, SPV106 ameliorated short- and long-term OL deficits. At 9 months of age, SPV106 had no effect on OL, whereas embelin ameliorated OL deficits. This work reveals a complex role for PCAF throughout AD progression, initially benefitting memory but detrimental as neuropathology becomes more severe. Therefore, memory deficits in AD may not always be ameliorated by HAT activation, and greater insight into the interactions between HATs, AD pathology, and cognition is necessary.
URI: http://hdl.handle.net/10214/17368
Date: 2019-08-29
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