Age-dependent Attenuation of Spatial Memory Deficits by the Histone Acetyltransferase P300/CBP-associated Factor (PCAF) in 3xTG Alzheimer's Disease Mice

Overview

Journal Learn Mem

Specialty Neurology

Date 2022 Feb 16

PMID 35169045

Authors

Samantha D Creighton

Kristen H Jardine

Alexa Desimone

Megan Zmetana

Sabrina Castellano

Ciro Milite

Gianluca Sbardella

Boyer D Winters

Affiliations

Soon will be listed here.

Abstract

Histone acetylation, catalyzed by histone acetyltransferases, has emerged as a promising therapeutic strategy in Alzheimer's disease (AD). By longitudinally characterizing spatial memory at 3, 6, and 9 mo of age, we show that acute activation and inhibition of the histone acetyltransferase PCAF remediated memory impairments in 3xTG-AD mice in an age-related bidirectional manner. At 3 and 6 mo of age, PCAF activation ameliorated memory deficits. At 9 mo of age, PCAF activation had no effect on spatial memory, whereas PCAF inhibition improved memory deficits in females. This work reveals a complex potential therapeutic role for PCAF in AD, initially benefitting memory but becoming detrimental as the disease progresses.

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References

Ruitenberg A, Ott A, van Swieten J, Hofman A, Breteler M . Incidence of dementia: does gender make a difference?. Neurobiol Aging. 2001; 22(4):575-80. DOI: 10.1016/s0197-4580(01)00231-7. View

Kuo M, Allis C . Roles of histone acetyltransferases and deacetylases in gene regulation. Bioessays. 1998; 20(8):615-26. DOI: 10.1002/(SICI)1521-1878(199808)20:8<615::AID-BIES4>3.0.CO;2-H. View

Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S, Agis-Balboa R . Altered histone acetylation is associated with age-dependent memory impairment in mice. Science. 2010; 328(5979):753-6. DOI: 10.1126/science.1186088. View

Vecsey C, Hawk J, Lattal K, Stein J, Fabian S, Attner M . Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB:CBP-dependent transcriptional activation. J Neurosci. 2007; 27(23):6128-40. PMC: 2925045. DOI: 10.1523/JNEUROSCI.0296-07.2007. View

Moodley K, Minati L, Contarino V, Prioni S, Wood R, Cooper R . Diagnostic differentiation of mild cognitive impairment due to Alzheimer's disease using a hippocampus-dependent test of spatial memory. Hippocampus. 2015; 25(8):939-51. DOI: 10.1002/hipo.22417. View

Park S, Lee Y, Seong A, Lee J, Jun W, Yoon H . Selective inhibition of PCAF suppresses microglial-mediated β-amyloid neurotoxicity. Int J Mol Med. 2013; 32(2):469-75. DOI: 10.3892/ijmm.2013.1407. View

Day J, Sweatt J . Epigenetic treatments for cognitive impairments. Neuropsychopharmacology. 2011; 37(1):247-60. PMC: 3238093. DOI: 10.1038/npp.2011.85. View

Rocca W, Amaducci L, Schoenberg B . Epidemiology of clinically diagnosed Alzheimer's disease. Ann Neurol. 1986; 19(5):415-24. DOI: 10.1002/ana.410190502. View

Fischer A, Sananbenesi F, Wang X, Dobbin M, Tsai L . Recovery of learning and memory is associated with chromatin remodelling. Nature. 2007; 447(7141):178-82. DOI: 10.1038/nature05772. View

10.

Ricobaraza A, Cuadrado-Tejedor M, Marco S, Perez-Otano I, Garcia-Osta A . Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease. Hippocampus. 2010; 22(5):1040-50. DOI: 10.1002/hipo.20883. View

11.

Chatterjee S, Cassel R, Schneider-Anthony A, Merienne K, Cosquer B, Tzeplaeff L . Reinstating plasticity and memory in a tauopathy mouse model with an acetyltransferase activator. EMBO Mol Med. 2018; 10(11). PMC: 6220301. DOI: 10.15252/emmm.201708587. View

12.

Mendell A, Creighton S, Wilson H, Jardine K, Isaacs L, Winters B . Inhibition of 5α Reductase Impairs Cognitive Performance, Alters Dendritic Morphology and Increases Tau Phosphorylation in the Hippocampus of Male 3xTg-AD Mice. Neuroscience. 2020; 429:185-202. DOI: 10.1016/j.neuroscience.2020.01.011. View

13.

Caccamo A, Maldonado M, Bokov A, Majumder S, Oddo S . CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2010; 107(52):22687-92. PMC: 3012497. DOI: 10.1073/pnas.1012851108. View

14.

Sbardella G, Castellano S, Vicidomini C, Rotili D, Nebbioso A, Miceli M . Identification of long chain alkylidenemalonates as novel small molecule modulators of histone acetyltransferases. Bioorg Med Chem Lett. 2008; 18(9):2788-92. DOI: 10.1016/j.bmcl.2008.04.017. View

15.

Beraldo F, Palmer D, Memar S, Wasserman D, Lee W, Liang S . MouseBytes, an open-access high-throughput pipeline and database for rodent touchscreen-based cognitive assessment. Elife. 2019; 8. PMC: 6934379. DOI: 10.7554/eLife.49630. View

16.

Graff J, Tsai L . Histone acetylation: molecular mnemonics on the chromatin. Nat Rev Neurosci. 2013; 14(2):97-111. DOI: 10.1038/nrn3427. View

17.

Hirata-Fukae C, Li H, Hoe H, Gray A, Minami S, Hamada K . Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model. Brain Res. 2008; 1216:92-103. DOI: 10.1016/j.brainres.2008.03.079. View

18.

Guo J, Ma D, Mo H, Ball M, Jang M, Bonaguidi M . Neuronal activity modifies the DNA methylation landscape in the adult brain. Nat Neurosci. 2011; 14(10):1345-51. PMC: 3183401. DOI: 10.1038/nn.2900. View

19.

Govindarajan N, Rao P, Burkhardt S, Sananbenesi F, Schluter O, Bradke F . Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer's disease. EMBO Mol Med. 2012; 5(1):52-63. PMC: 3569653. DOI: 10.1002/emmm.201201923. View

20.

de Ruijter A, van Gennip A, Caron H, Kemp S, van Kuilenburg A . Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. 2002; 370(Pt 3):737-49. PMC: 1223209. DOI: 10.1042/BJ20021321. View