Epigenetic mechanisms re-establish access to long-term memory after neuronal loss

a long-term memory and epigenetic technology, applied in the field of epigenetic mechanisms reestablish access to long-term memory after neuronal loss, to achieve the effect of increasing histone acetylation

Inactive Publication Date: 2012-02-16
PRESIDENT & FELLOWS OF HARVARD COLLEGE +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0005]In some embodiments the invention provides methods for inducing an increase in histone acetylation. In some aspects the invention provides methods for the change in level of methylation in histones. One aspect of the invention is the increase in histone acetylation through the administration of inhibitors of histone-deacetylases. The administration of inhibitors of histone-deacetylases induced sprouting of dendrites, an increased number of synapses, and reinstated learning behavior and access to long-term memories. In some embodiments the invention provides epigenetic approaches as a therapeutic avenue for neurodegenerative diseases associated with learning and memory impairment including the recovery of long-term memories in patients with dementia.

Problems solved by technology

Neurodegenerative diseases of the central nervous system are often associated with impaired learning and memory, eventually leading to dementia.

Method used

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  • Epigenetic mechanisms re-establish access to long-term memory after neuronal loss
  • Epigenetic mechanisms re-establish access to long-term memory after neuronal loss
  • Epigenetic mechanisms re-establish access to long-term memory after neuronal loss

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Effect test

example 1

The Effect of EE on Learning Behavior after Neuronal Loss

[0143]To investigate the effect of EE on learning behavior after neuronal loss had already occurred, p25 was induced in 11-month old CK-p25 Tg mice for 6 weeks. Afterwards p25 expression was repressed (3) and one group of CK-p25 Tg mice was subjected to EE, whereas the other group was not enriched. Subsequently all mice, including a control group that did not express p25, were subjected to fear conditioning and water maze learning (n=8 / group) (FIG. 1a). Despite a comparable extent of brain atrophy (P=0.2435 enriched vs. nonenriched CK-p25 Tg mice; Pb, FIG. 7a). Non-enriched CK-p25 Tg mice displayed impaired freezing behavior, when compared to control mice (P=0.0337), indicating impaired associative learning. Enriched CK-p25 Tg mice showed significantly more freezing when compared to the non-enriched group (Pc). In addition, the escape latency in the water maze test was significantly impaired in non-enriched CK-p25 Tg mice when...

example 2

Experimental Model for the Investigation of Long-Term Memories

[0146]To establish an experimental model that allows investigation of the fate of long-term memories, 11-month old CK-p25 Tg and control mice were trained in the fear conditioning paradigm and returned to their home cages for 4 weeks to allow the consolidation of hippocampus-independent long-term memories. Subsequently p25 was induced for either 3 (Exp. 1) or 6 weeks (Exp. 2) before the mice were subjected to the memory test. These time points were chosen because, in contrast to 6-week induction, after 3 weeks of p25 expression no overt pathology was observed (3) (FIG. 2a). In Exp. 1, CK-p25 Tg mice (n=8) showed similar freezing than control mice (n=9; P=0.863) (FIG. 2b; Exp.1). In contrast, CK-p25 Tg mice induced for 6 weeks (n=9) showed significant reduction in freezing behavior during the memory test performed 10 weeks after the training when compared to the control group (n=16; Pb; Exp.2). The loss of consolidated lon...

example 3

Mechanism Underlying EE

[0150]Other than a few genes involved in synaptic function, relatively little is known about the mechanism underlying EE (12-14). Since histone acetylation, an epigenetic mechanism regulating gene expression via chromatin remodeling, has recently been implicated in synaptic plasticity and learning behavior (15-18), the induction of a transcriptional program by EE that leads to activation of plasticity genes was evaluated. Wild type mice were subjected to EE and hippocampal and cortical brain lysates were obtained 3, 24 h or 2 weeks later (n=3 / group) by acid extraction and probed with antibodies detecting histone-tail modification that indicate active chromatin. Increases in hippocampal H3 (K-9, K14) and H4 (K-5) and in cortical H3 (K-9) and H4 (K-5) acetylation were observed. In addition increased methylation of H3 (K4) was observed in cortical lysates. No changes in H4 acetylation were observed when the Ac-H4 (K5,8,12,16) antibody was used, which is likely du...

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Abstract

The invention relates to methods and products for enhancing and improving recovery of lost memories. In particular the methods are accomplished through the increase of histone acetylation.

Description

RELATED APPLICATION[0001]This application is a continuation application and claims the benefit under 35 U.S.C. §120 of U.S. application Ser. No. 11 / 998,834, entitled “EPIGENETIC MECHANISMS RE-ESTABLISH ACCESS TO LONG-TERM MEMORY AFTER NEURONAL LOSS” filed on Nov. 30, 2007, which is herein incorporated by reference in its entirety. application Ser. No. 11 / 998,834 claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application Ser. No. 60 / 861,883, entitled “EPIGENETIC MECHANISMS RE-ESTABLISH ACCESS TO LONG-TERM MEMORY AFTER NEURONAL LOSS” filed Nov. 30, 2006, which is herein incorporated by reference in its entirety.FEDERALLY SPONSORED RESEARCH[0002]This invention was made with Government support under NIH NS051874. Accordingly, the Government has certain rights in this invention.BACKGROUND OF INVENTION[0003]Brain atrophy occurs during normal aging and is an early feature of neurodegenerative diseases associated with impaired learning and memory. Only recently have mouse model...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/167A61K31/404A61K31/166A61K31/353A61K48/00A61P25/00A61K39/395A61K31/7068A61K31/19A61K31/4406A61P25/28A61K31/4192A61K31/7088
CPCA61K31/164A61K31/19A61K31/215A61K31/7068A61K31/4192A61K31/7052A61K31/404A61P25/00A61P25/28
Inventor TSAI, LI-HUEIFISCHER, ANDREHAGGARTY, STEPHENTANG, WEIPINGSCHREIBER, STUART L.
Owner PRESIDENT & FELLOWS OF HARVARD COLLEGE
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