METHOD TO RESTORE OR IMPROVE COGNITIVE FUNCTIONS
The present invention relates to the field of memory and cognitive functions. Here the inventors show that memory stimulations induce autophagy in the mouse hippocampus, while local pharmacological and genetic modulations of hippocampal autophagy strongly influence memory acquisition. More, the inventors observe that hippocampal autophagy declines during aging and they find that restoring autophagy specifically in the hippocampus of aged mice, following autophagy inducers (such as TAT-Beclin-1), can significantly reverse age-related memory decline. Their results reveal a novel physiological role of autophagy in regulating hippocampal-dependent memory functions, and demonstrate the potential therapeutic benefits of modulating autophagy in order to prevent and/or reverse the deleterious effects of aging on cognitive function. The present invention relates to an activator of the autophagy for use in the restoration and/or improvement of cognitive functions in a subject in need thereof.
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5 . The method of claim 11 , wherein the activator is selected from the group consisting of Earle's balanced salt solution (EBSS), Brefeldin A, Thapsigargin, Tunicamycin, Rapamycin, CCI-779, RAD001, AP23576, Small molecule enhancers rapamycin (SMER), Trehalose, L-690,330, Carbamazepine, Valproic acid sodium salt, N-Acetyl-D-sphingosine (C2-ceramide), Penitrem A, Calpastatin, Xestospongin B, Akebia saponin, Amiodarone hydrochloride, ATG13, GF 109203X synthetic, GF 109203X hydrochloride, N-Hexanoyl-D-sphingosine, MRT68921 dihydrochloride, Niclosamide, Qc1, Rottlerin, STF-62247, Tamoxifen, Temsirolimus, ULK Active, Z36 and Hydroxycitrate.
6 . The method of claim 11 , wherein the activator is Beclin 1.
7 . The method of claim 11 , wherein the activator is a peptide comprising an amino acid sequence of formula (I) (SEQ ID NO: 2):
Xaa1-N-A-T-F-Xaa2-Xaa3-Xaa4-Xaa5,
wherein:
Xaa1, Xaa2, Xaa3, Xaa4 and Xaa5 are each an amino acid independently selected from the group consisting of Alanine (A), Arginine (R), Asparagine (N), Aspartic acid (D), Cysteine (C), Glutamic acid (E), Glutamine (Q), Glycine (G), Histidine (H), Isoleucine (I), Leucine (L), Lysine (K), Methionine (M), Phenylalanine (F), Proline (P), Serine (S), Threonine (T), Tryptophan (W), Tyrosine (Y), Valine (V), allyl glycine (AllylGly), norleucine, norvaline, biphenylalanine (Bip), citrulline (Cit), 4-guanidinophenylalanine (Phe(Gu)), homoarginine (hArg), homolysine (hLys), 2-naphtylalanine (2-Nal), ornithine (Orn) Of and pentafluorophenylalanine.
8 . The method of claim 7 wherein the activator is the peptide TAT-Beclin 1 of SEQ ID NO:37.
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11 . A method of i) restoring and/or improving one or more cognitive functions, ii) treating a cognitive disease, iii) preventing or reversing the deleterious effects of aging on cognitive function, and/or iv) restoring and/or improving age-related memory decline or age-related memory loss in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an activator of autophagy.