ApoE4 and Aβ Oligomers Reduce BDNF Expression via HDAC Nuclear Translocation

Abstract

Apolipoprotein E4 (ApoE4) is a major genetic risk factor for several neurodegenerative disorders, including Alzheimer's disease (AD). Epigenetic dysregulation, including aberrations in histone acetylation, is also associated with AD. We show here for the first time that ApoE4 increases nuclear translocation of histone deacetylases (HDACs) in human neurons, thereby reducing BDNF expression, whereas ApoE3 increases histone 3 acetylation and upregulates BDNF expression. Amyloid-β (Aβ) oligomers, which have been implicated in AD, caused effects similar to ApoE4. Blocking low-density lipoprotein receptor-related protein 1 (LRP-1) receptor with receptor-associated protein (RAP) or LRP-1 siRNA abolished the ApoE effects. ApoE3 also induced expression of protein kinase C ε (PKCε) and PKCε retained HDACs in the cytosol. PKCε activation and ApoE3 supplementation prevented ApoE4-mediated BDNF downregulation. PKCε activation also reversed Aβ oligomer- and ApoE4-induced nuclear import of HDACs, preventing the loss in BDNF. ApoE4 induced HDAC6-BDNF promoter IV binding, which reduced BDNF exon IV expression. Nuclear HDAC4 and HDAC6 were more abundant in the hippocampus of ApoE4 transgenic mice than in ApoE3 transgenic mice or wild-type controls. Nuclear translocation of HDA6 was also elevated in the hippocampus of AD patients compared with age-matched controls. These results provide new insight into the cause of synaptic loss that is the most important pathologic correlate of cognitive deficits in AD.

Protein Kinase Cϵ (PKCϵ) Promotes Synaptogenesis through Membrane Accumulation of the Postsynaptic Density Protein PSD-95

“…HuD increases as a result of PKC⑀ activation after learning (67) and stabilizes the mRNA for BDNF, nerve growth factor (NGF), and neurotrophin-3 (NT-3) (19). PKC⑀ activation induces the synthesis of BDNF (10,20,47), and BDNF induces transport of PSD-95 to the dendrites (68), which is required for maintenance of mature spines (69). Deficits of PKC⑀ function could also contribute to the synapse loss in Alzheimer disease (15), whereas the therapeutic elimination of such deficits may offer a strategy for the treatment of synaptic loss in Alzheimer disease and other synaptic disorders.…”

“…PKC activation induces protein synthesis required for long term memory (12,18). PKC⑀ activation is also required for HuD-mediated mRNA stabilization of neurotrophic factors (19) and apoE-mediated epigenetic regulation of BDNF (20). PKC activation induces translocation of calcium/ calmodulin-dependent kinase II (CaMKII) 2 to synapses (21) where it participates in PSD-95-induced synaptic strengthening (22).…”

“…Some of these benefits have been attributed to induction of neurotrophic factors such as BDNF or the activation of anti-A␤ repair pathways and anti-apoptotic activity (10,13,20,25). However, the biochemical mechanisms by which PKC⑀ induces synaptogenesis and mediates neuroprotection are still not fully understood.…”

Histone acetylation in neuronal (dys)function

“…Recent findings also involved changes in HDAC 4 and HDAC 6 nuclear localization that depend on the AD genetic risk factor APOE 4 (86). APOE ε4 increases by a 2-3 fold chance to develop early onset of AD when it is represented as a single allele and by over 12-fold when two APOE ε4 alleles are expressed.…”

The Transcription Factor XBP1 in Memory and Cognition: implications in Alzheimer’s Disease

“…Alternatively, a disruption of BDNF signaling would likely reduce or prevent XBP1-dependent amelioration of AD-like pathology (19). In vivo and in vitro studies have demonstrated that oligomeric Aβ alters BDNF expression/function by downregulating its transcripts or impairing axonal transport, with subsequent adverse effects (159)(160)(161)(162)(163)(164)(165). Oligomeric Aβ also reduces BDNF secretion by dendritic cells in humans, thereby decreasing neurotrophic supports for neurons and causing brain damage (166).…”