Tip60 protects against amyloid-β-induced transcriptomic alterations via different modes of action in early versus late stages of neurodegeneration.
Tip60 protects against amyloid-β-induced transcriptomic alterations via different modes of action in early versus late stages of neurodegeneration.
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DOI：
10.1016/j.mcn.2020.103570
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Elefant F
中科院分区：
文献类型：
--
作者：
Zhang H;Karisetty BC;Bhatnagar A;Armour EM;Beaver M;Roach TV;Mortazavi S;Mandloi S;Elefant F
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder hallmarked by amyloid-β (Aβ) plaque accumulation, neuronal cell death, and cognitive deficits that worsen during disease progression. Histone acetylation dysregulation, caused by an imbalance between reduced histone acetyltransferases (HAT) Tip60 and increased histone deacetylase 2 (HDAC2) levels, can directly contribute to AD pathology. However, whether such AD-associated neuroepigenetic alterations occur in response to Aβ peptide production and can be protected against by increasing Tip60 levels over the course of neurodegenerative progression remains unknown. Here we profile Tip60 HAT/HDAC2 dynamics and transcriptome-wide changes across early and late stage AD pathology in the Drosophila brain produced solely by human amyloid-β42. We show that early Aβ42 induction leads to disruption of Tip60 HAT/HDAC2 balance during early neurodegenerative stages preceding Aβ plaque accumulation that persists into late AD stages. Correlative transcriptome-wide studies reveal alterations in biological processes we classified as transient (early-stage only), late-onset (late-stage only), and constant (both). Increasing Tip60 HAT levels in the Aβ42 fly brain protects against AD functional pathologies that include Aβ plaque accumulation, neural cell death, cognitive deficits, and shorter life-span. Strikingly, Tip60 protects against Aβ42-induced transcriptomic alterations via distinct mechanisms during early and late stages of neurodegeneration. Our findings reveal distinct modes of neuroepigenetic gene changes and Tip60 neuroprotection in early versus late stages in AD that can serve as early biomarkers for AD, and support the therapeutic potential of Tip60 over the course of AD progression.
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DOI：
10.3791/50107
发表时间：
2014-08-07
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Malik BR;Hodge JJ
通讯作者：
Hodge JJ
影响因子：
3.7
作者：
Iijima K;Chiang HC;Hearn SA;Hakker I;Gatt A;Shenton C;Granger L;Leung A;Iijima-Ando K;Zhong Y
通讯作者：
Zhong Y
影响因子：
4.8
作者：
Lanchec, Erwan;Desilets, Antoine;Lavoie, Christine
通讯作者：
Lavoie, Christine
影响因子：
5.3
作者：
Krashes, Michael J.;Waddell, Scott
通讯作者：
Waddell, Scott
DOI：
10.1093/brain/awy189
发表时间：
2018-09-01
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Grothe MJ;Sepulcre J;Gonzalez-Escamilla G;Jelistratova I;Schöll M;Hansson O;Teipel SJ;Alzheimer’s Disease Neuroimaging Initiative
通讯作者：
Alzheimer’s Disease Neuroimaging Initiative