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May 07, 2009

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Memories stolen by Alzheimer’s may be retrievable: study

May 7, 2009
Courtesy MIT
and World Science staff

Re­search­ers have pin­pointed a gene said to be re­spon­si­ble for a 2007 break­through in which mice with an Alz­hei­mer’s dis­ease-like con­di­tion re­gained lost mem­o­ries and learn­ing abil­ities.

In the new re­search, re­ported in the May 7 is­sue of the sci­en­tif­ic jour­nal Na­ture, Mas­sa­chu­setts In­sti­tute of Tech­nol­o­gy neu­ro­sci­ent­ist Li-Huei Tsai and col­leagues found that drugs that work on the gene HDAC2 re­verse the ef­fects of Alzheimer’s and boost cog­ni­tive func­tion in mice.

Re­search­ers said the find­ings serve as ev­i­dence that mem­o­ries lost to Alzheimer’s and re­lat­ed con­di­tions may not be gone for good. Rath­er, they could have got­ten stuck deep in the brain wait­ing for the prop­er medicines to help dis­lodge them.

The HDAC2 gene, and a mol­e­cule it pro­duces, “are prom­is­ing tar­gets for treat­ing mem­o­ry im­pair­men­t,” Tsai said. The gene con­trols the ac­ti­vity of many oth­er genes “im­pli­cated in plas­ticity — the brain’s abil­ity to change in re­sponse to ex­pe­ri­ence — and mem­o­ry forma­t­ion.”

The gene causes last­ing changes in how oth­er genes be­have, which is probably nec­es­sary to in­crease num­bers of con­nec­tions be­tween brain cells, she added. The re­search­ers treated mice with Alzheimer’s-like symp­toms us­ing so-called his­tone deacety­lase, or HDAC, in­hibitors, a family of 11 en­zymes that seem to act as mas­ter reg­u­la­tors of gene ac­ti­vity. The drugs are in ex­pe­ri­men­tal stages and are not avail­a­ble for pa­tient use.

“Har­ness­ing the ther­a­peu­tic po­ten­tial of HDAC in­hibitors re­quires knowl­edge of the spe­cif­ic HDAC family mem­ber or mem­bers linked to cog­ni­tive en­hance­men­t,” Tsai said. “We have now iden­ti­fied HDAC2 as the most likely tar­get of the HDAC in­hibitors” that fa­cil­i­tate plas­ticity and mem­o­ry forma­t­ion.

A per­son’s DNA is pack­aged as part of a ma­te­ri­al called chro­ma­tin, and cer­tain genes con­trol ar­rays of oth­er genes simply by re­struc­tur­ing the chro­ma­tin. The new re­search helps clar­i­fy how this pro­cess works in reg­u­lat­ing mem­o­ry, Tsai said. 

Sev­er­al HDAC in­hibitors are cur­rently in clin­i­cal tri­als as an­ti­can­cer agents. Re­search­ers have also re­ported prom­is­ing re­sults with HDAC in­hibitors in mouse ver­sions of Hunt­ing­ton’s dis­ease. 

In the chro­ma­tin, mol­e­cules called his­tones act as spools around which DNA winds. Hi­s­tones are mod­i­fied in var­i­ous ways, in­clud­ing through a pro­cess called ac­e­tyla­t­ion, which in turn mod­i­fies chro­ma­tin shape and struc­ture. HDAC in­hibitors pro­mote this pro­cess. Cer­tain HDAC in­hibitors open up chro­ma­tin. This al­lows genes to be­come ac­tive which had been too tightly pack­aged to go in­to opera­t­ion.

The re­search­ers con­ducted learn­ing and mem­o­ry tasks us­ing ge­net­ic­ally en­gi­neered mice that were in­duced to lose many brain cells. Fol­low­ing Alzheimer’s-like brain shrink­age, the mice acted as though they had forgot­ten tasks they had pre­vi­ously learn­ed. But af­ter tak­ing HDAC in­hibitors, the mice re­gained their long-term mem­o­ries and abil­ity to learn new tasks, ac­cord­ing to Tsai. In ad­di­tion, mice ge­net­ic­ally en­gi­neered to pro­duce no HDAC2 at all ex­hib­ited en­hanced mem­o­ry forma­t­ion.

The fact that long-term mem­o­ries can be re­cov­ered by el­e­vat­ed his­tone ac­e­tyla­t­ion sup­ports the idea that ap­par­ent mem­o­ry “loss” is really a re­flec­tion of in­ac­ces­si­ble mem­o­ries, Tsai said. “These find­ings are in line with a phe­nom­e­non known as ‘fluc­tu­at­ing mem­o­ries,’ in which de­ment­ed pa­tients ex­pe­ri­ence tem­po­rary per­i­ods of ap­par­ent clar­ity,” she added.

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Researchers have pinpointed a gene said to be responsible for a 2007 breakthrough in which mice with Alzheimer’s disease symptoms regained long-term memories and the ability to learn. In the new research, reported in the May 7 issue of the scientific journal Nature, Massachusetts Institute of Technology neuroscientist Li-Huei Tsai and colleagues found that drugs that work on the gene HDAC2 reverse the effects of Alzheimer’s and boost cognitive function in mice. Researchers said the findings serve as evidence that memories lost to Alzheimer’s and related conditions aren’t gone for good. Rather, they have gotten stuck deep in the brain waiting for the proper medicines to dislodge them. The HDAC2 gene, and a molecule it produces, “are promising targets for treating memory impairment,” Tsai said. The gene controls the activity of many other genes “implicated in plasticity — the brain’s ability to change in response to experience — and memory formation.” The gene causes lasting changes in how other genes behave, which is probably necessary to increase numbers of connections between brain cells, she added. The researchers treated mice with Alzheimer’s-like symptoms using so-called histone deacetylase, or HDAC, inhibitors, a family of 11 enzymes that seem to act as master regulators of gene activity. The drugs are in experimental stages and are not available for patients’ use. “Harnessing the therapeutic potential of HDAC inhibitors requires knowledge of the specific HDAC family member or members linked to cognitive enhancement,” Tsai said. “We have now identified HDAC2 as the most likely target of the HDAC inhibitors that facilitate synaptic plasticity and memory formation. A person’s DNA is packaged as part of a material called chromatin, and certain genes control arrays of other genes simply by restructuring the chromatin. The new research helps clarify how this process works in regulating memory, Tsai said. Several HDAC inhibitors are currently in clinical trials as novel anticancer agents and may enter the pipeline for other diseases in the coming two to four years. Researchers have had promising results with HDAC inhibitors in mouse models of Huntington’s disease. In the chromatin, molecules called histones act as spools around which DNA winds. Histones are modified in various ways, including through a process called acetylation, which in turn modifies chromatin shape and structure. HDAC inhibitors promote this process. Certain HDAC inhibitors open up chromatin. This allows genes to become active which had been too tightly packaged to go into operation. The researchers conducted learning and memory tasks using genetically engineered mice that were induced to lose many brain cells. Following Alzheimer’s-like brain shrinkage, the mice acted as though they had forgotten tasks they had previously learned. But after taking HDAC inhibitors, the mice regained their long-term memories and ability to learn new tasks, according to Tsai. In addition, mice genetically engineered to produce no HDAC2 at all exhibited enhanced memory formation. The fact that long-term memories can be recovered by elevated histone acetylation supports the idea that apparent memory “loss” is really a reflection of inaccessible memories, Tsai said. “These findings are in line with a phenomenon known as ‘fluctuating memories,’ in which demented patients experience temporary periods of apparent clarity,” she added.