Scientists Remove Gene Blockade, Boost Cognition in Alzheimer Disease

http://www.genengnews.com/gen-news-h...ease/81246433/


Scientists say histone deacetylase 2 (HDAC2)-selective inhibitors may represent a therapeutic approach to slowing cognitive decline in patients with neurodegenerative disorders such as Alzheimer disease (AD). Researchers at the Massachusetts Institute of Technology’s (MIT) Picower Institute for Learning and Memory and Howard Hughes Medical Institute found increased levels of HDAC2 in two mouse models of AD and in human AD patients. These increased levels of the deacetylating enzyme were associated with the reductions in histone acetylation and expression levels of key learning-related genes.


...Epigenetic modifications in the nervous system that are mediated by histone acetylation have been unequivocally associated with facilitating learning and memory, the researchers state. Multiple studies have in addition reported that reduced histone acetylation is associated with cognitive decline in animal models of neurodegeneration including AD.



The results thus far indicated that HDAC2 is directly involved in decreasing the expression of neuroplasticity genes, which may contribute to cognitive deficits during neurodegeneration. ..

Initial analyses confirmed that HDAC2 levels had in the CK-225 mice were reduced to those found in control mice, whereas protein levels of HDAC1 and HDAC3 were unchanged. Encouragingly, the lower HDAC2 levels were associated with increased H4K12 histone acetylation on most of the neuroplasticity genes evaluated, and expression that comparable or higher than that in control mice.



The overall results provide some hope that it may be possible to hold back cognitive deficits in AD patients, they state. “Our finding that HDAC2 inhibition probably reinstates transcriptional, morphological, and synaptic plasticity in the surviving neurons of the neurodegenerating brain raises hope that such plasticity is not irrevocably lost but merely constrained by the epigenetic blockade.”

The findings may also help explain why cognitive impairments in patients with AD who are involved in clinical trials persist despite successful amyloid-β clearance. “Once the epigenetic blockade is in place, reducing amyloid-β generation and deposition alone may not be sufficient to rescue against cognitive dysfunction,” the team suggests. “A more efficacious strategy may therefore lie in the combination of amyloid-beta reduction with the inhibition of HDAC2."

HDAC Inhibitors



Drugs: Valproic acid and

Sulindac (anti inflammatory drug)


Natural compounds:
Curcumin

also an HDAC inhibitor. It inhibits class I HDAC enzymes

http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum




Sulforaphane

The highest natural concentration of sulforaphane is found in" brocco sprouts" (can be found in small plastic containers next to alfalfa sprouts, etc. in market) The metabolism products of this compound are natural HDAC inhibitors. Sulforaphane is also available in supplement form.

http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum

http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum

http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum





Grouppe Kurosawa, Medicine in the Public Interest
Parthenolide (Natural HDAC inhibitor)--feverfew
EGCG, Resveratrol. Quercetin are also listed as HDAC inhibitors