Striatal ZBTB16 Is Associated With Cognitive Deficits in Alzheimer Disease Mice
2
조회
0
다운로드
2
인용
0
참고문헌
키워드
초록
Purpose: In Alzheimer disease (AD), brain regions such as the cortex and the hippocampus show abundant amyloid load which correlates with cognitive function decline. Prior to the significant development of AD pathophysiology, patients report the manifestation of neuropsychiatric symptoms, indicating a functional interplay between basal ganglia structures and hippocampal regions. Zinc finger and BTB domain-containing protein 16 (ZBTB16) is a transcription factor that controls the expression of downstream genes and the involvement of ZBTB16 in the striatum undergoing pathological aging in AD and the resulting behavioral phenotypes has not yet been explored. Methods: To study molecular alterations in AD pathogenesis, we analyzed the brain from amyloid precursor protein (APP)/ presenilin 1 (PS1) transgenic mice. The molecular changes in the striatal region of the brain were analyzed via the immunoblotting, and the quantitative RNA sequencing. The cognitive impairments of APP/PS1 mice were assessed via 3 behavioral tests: 3-chamber test, Y-maze test, and noble object recognition test. And multielectrode array experiments for the analysis of the neuronal activity of the striatum in APP/PS1 mice was performed. Results: We found that the alteration in ZBTB16 levels that occurred in the early ages of the pathologically aging striatum coalesces with the disruption of transcriptional dysregulation while causing social memory deficits, anxiety-like behavior. The early ZBTB16 knockdown treatment in the striatum of APP/PS1 mice rescued cognition that continued into later age. Conclusions: This study demonstrates that perturbation of transcriptional regulation of ZBTB16 during pathological aging may influence cognitive impairments and reveals a potent approach to targeting the transcriptional regulation of the striatum for the treatment of AD.
Abstract
Purpose: In Alzheimer disease (AD), brain regions such as the cortex and the hippocampus show abundant amyloid load which correlates with cognitive function decline. Prior to the significant development of AD pathophysiology, patients report the manifestation of neuropsychiatric symptoms, indicating a functional interplay between basal ganglia structures and hippocampal regions. Zinc finger and BTB domain-containing protein 16 (ZBTB16) is a transcription factor that controls the expression of downstream genes and the involvement of ZBTB16 in the striatum undergoing pathological aging in AD and the resulting behavioral phenotypes has not yet been explored. Methods: To study molecular alterations in AD pathogenesis, we analyzed the brain from amyloid precursor protein (APP)/ presenilin 1 (PS1) transgenic mice. The molecular changes in the striatal region of the brain were analyzed via the immunoblotting, and the quantitative RNA sequencing. The cognitive impairments of APP/PS1 mice were assessed via 3 behavioral tests: 3-chamber test, Y-maze test, and noble object recognition test. And multielectrode array experiments for the analysis of the neuronal activity of the striatum in APP/PS1 mice was performed. Results: We found that the alteration in ZBTB16 levels that occurred in the early ages of the pathologically aging striatum coalesces with the disruption of transcriptional dysregulation while causing social memory deficits, anxiety-like behavior. The early ZBTB16 knockdown treatment in the striatum of APP/PS1 mice rescued cognition that continued into later age. Conclusions: This study demonstrates that perturbation of transcriptional regulation of ZBTB16 during pathological aging may influence cognitive impairments and reveals a potent approach to targeting the transcriptional regulation of the striatum for the treatment of AD.
참고문헌 (27)
- Sweeney MD, "Vascular dysfunction-The disregarded partner of Alzheimer’s disease", Alzheimers Dement, 15, pp.158~167 (2019)
- Herrup K, "The case for rejecting the amyloid cascade hypothesis", Nat Neurosci, 18, pp.794~799 (2015)
- Huguet G, "Altered expression of dopaminergic cell fate regulating genes prior to manifestation of symptoms in a transgenic rat model of Huntington’s disease", Brain Res, 1712, pp.101~108 (2019)
- Usui N, "Zbtb16 regulates social cognitive behaviors and neocortical development", Transl Psychiatry, 11, pp.242~ (2021)
- Lee S, "Dysfunction of striatal MeCP2 is associated with cognitive decline in a mouse model of Alzheimer’s disease", Theranostics, 12, pp.1404~1418 (2022)
- Khan AW, "MeCP2 interacts with chromosomal microRNAs in brain", Epigenetics, 12, pp.1028~1037 (2017)
- He Y, "Spatiotemporal DNA methylome dynamics of the developing mouse fetus", Nature, 583, pp.752~759 (2020)
- Puszyk W, "The epigenetic regulator PLZF represses L1 retrotransposition in germ and progenitor cells", EMBO J, 32, pp.1941~1952 (2013)
- Chen L, "MeCP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome", Proc Natl Acad Sci U S A, 112, pp.5509~5514 (2015)
- Liu H, "DNA methylation atlas of the mouse brain at single-cell resolution", Nature, 598, pp.120~128 (2021)
- Pennartz CM, "The hippocampal-striatal axis in learning, prediction and goal-directed behavior", Trends Neurosci, 34, pp.548~559 (2011)
- Abd-Elrahman KS, "mGluR5 regulates ZBTB16 pathway of autophagy in Alzhimer’s disease in a sex-specific manner", Faseb Journal, 33(Suppl 1), pp.810.5~ (2019)
- Keenan AB, "ChEA3 : transcription factor enrichment analysis by orthogonal omics integration", Nucleic Acids Res, 47, pp.W212~W224 (2019)
- Liu TM, "Concise review : balancing stem cell self-renewal and differentiation with PLZF", Stem Cells, 34, pp.277~287 (2016)
- Pelengaris S, "c-MYC : more than just a matter of life and death", Nat Rev Cancer, 2, pp.764~776 (2002)
- Gong D, "The roles of cyclin A2, B1, and B2 in early and late mitotic events", Mol Biol Cell, 21, pp.3149~3161 (2010)
- Gopinathan L, "Loss of Cdk2 and cyclin A2 impairs cell proliferation and tumorigenesis", Cancer Res, 74, pp.3870~3879 (2014)
- Yang Y, "Ectopic cell cycle events link human Alzheimer’s disease and amyloid precursor protein transgenic mouse models", J Neurosci, 26, pp.775~784 (2006)
- Varvel NH, "Abeta oligomers induce neuronal cell cycle events in Alzheimer’s disease", J Neurosci, 28, pp.10786~10793 (2008)
- Li L, "A comparative study of five mouse models of Alzheimer’s disease : cell cycle events reveal new insights into neurons at risk for death", Int J Alzheimers Dis, 2011, pp.171464~ (2011)
- Zhang T, "G-proteincoupled receptors regulate autophagy by ZBTB16-mediated ubiquitination and proteasomal degradation of Atg14L", Elife, 4, pp.e06734~ (2015)
- Obara K, "Atg14 : a key player in orchestrating autophagy", Int J Cell Biol, 2011, pp.713435~ (2011)
- Pankiv S, "p62", SQSTM1 binds directly to Atg8, J Biol Chem, pp.2007, 282[DOI]
- Stolz A, "Cargo recognition and trafficking in selective autophagy", Nat Cell Biol, 16, pp.495~501 (2014)
- Chun Y, "Autophagy : an essential degradation program for cellular homeostasis and life", Cells, 7, pp.278~ (2018)
- Lie PPY, "Axonal transport of late endosomes and amphisomes is selectively modulated by local Ca(2+)efflux and disrupted by PSEN1 loss of function", Sci Adv, 8, pp.eabj5716~ (2022)
- Liu R, "ATG14 controls SNARE-mediated autophagosome fusion with a lysosome", Autophagy, 11, pp.847~849 (2015)