gms | German Medical Science

Introduction: Emerging evidence suggests that epigenetic mechanisms significantly contribute to the pathogenesis of complex neurodegenerative diseases such as Alzheimer’s disease (AD). Although the neuronal population in the cerebral cortex and hippocampus is primarily vulnerable, involvement of non-neuronal cells such as astrocytes and microglia have been implicated in AD. Here, we report that substantial alterations of several histone modification marks are observed in the vulnerable brain regions of 5X FAD mice, a transgenic mouse model of Familial Alzheimer’s Disease in an age dependent manner.

Objectives: Microglial activation and concomitant over expression of several pro-inflammatory molecules including chemokines, chemokine receptors, complement and complement receptors are found at older (40 weeks) age of the FAD mice compared to wild type. The objective of this study was to elucidate the role epigenetic regulation plays in microglial activity during the development and progression of AD.

Materials & Methods: To specifically address the role of microglial epigenetics in AD pathology, we developed FAD mice with an inducible, microglia specific knock-out of either histone deacetylase (HDAC) 1 or 2 or both. AD pathology was studied through histological and protein biochemical quantification of Amyloid deposition as well as behavioral testing of learning & memory in animals. To further elucidate the specific impact of HDAC1 and 2 knockout, transcriptional effects as well as epigenetic effects were studied by RNAseq and ChIPseq on isolated microglia.

Results: The results indicate that microglia specific knock out of HDAC2 as well as double knock out of HDAC1 and 2 reduce the production of soluble monomeric Abeta 42 (Aβ42), the toxic proteolytic cleavage product of Amyloid Precursor Protein (APP) in the brain of FAD mice. Further Amyloid deposition in brains of double knockout animals is markedly reduced. In line with reduction of amyloid deposition, learning & memory in these mice are improved over non-knockout FAD mice at 12 months of age.

Conclusion: Epigenetic regulation of microglial function through HDAC1 and 2 plays a major role in AD disease progression. Microglia specific ablation of both genes markedly ameliorates AD pathology and improves learning and memory functions in a mouse model of AD.