ApoE4 and Aβ Oligomers Reduce BDNF Expression via HDAC Nuclear Translocation

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ApoE4 and Aβ Oligomers Reduce BDNF Expression via HDAC Nuclear Translocation

Postby ApropoE4 » Wed May 13, 2015 7:22 pm


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.

From an article:

BRNI has shown in pre-clinical studies that activating PKC with potent activators such as Bryostatin can prevent ApoE4 from inhibiting BDNF production. Bryostatin, by increasing PKC epsilon, has also been shown in previous pre-clinical studies to lower soluble A Beta oligomers that lead to plaque formation. Since A Beta oligomers also function like ApoE4 to interfere with DNA-controlled BDNF production through HDACs, Bryostatin could potentially block this A Beta oligomer effect as well. This would offer further Alzheimer's disease prevention potential. Elevated HDACs, lower PKC epsilon, reduced BDNF and increased A Beta oligomers, working together, compromise synaptic function, growth and maintenance in the absence of amyloid plaques and tangles.

Discoveries from the present study suggest that these same PKC activators in trials to treat Alzheimer's disease patients could potentially be given to healthy individuals who have the ApoE4 genes – even before Alzheimer's disease begins – thereby preventing the onset of debilitating dementia and brain degeneration.

"We are excited and encouraged by these results," said Alkon. "In essence, our findings suggest that Bryostatin could be used in some patients to prevent Alzheimer's disease before it ever begins."

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Re: ApoE4 and Aβ Oligomers Reduce BDNF Expression via HDAC Nuclear Translocation

Postby aphorist » Wed May 13, 2015 8:51 pm

I guess I fail to understand the mechanisms of action here, as presented in the article.

1. If LRP is involved in removing amyloid beta from neurons (pumping them out) and in alzheimer's patients LRP becomes oxizided and malfunctions, why would you want to block LRP in the first place?

2. If Lithium is seen as beneficial and that inhibits PKC/PKE, why would someone want to activate it?

I realize there are transient states in which these pathways/enzymes operate, but maybe I'm not understanding something here in the broader picture.

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