This fly paper catches genetic evidence that Rac inhibition slows memory decay, constitutively increased Rac activation accelerates memory decay, and that cofilin hyperactivation gives rise to the same phenotype as seen with Rac inhibition. The authors conclude that the “Rac-regulated PAK/LIMK/cofilin pathway might be critical in influencing memory decay.” The specificity for Rac activation defects in an active forgetting process relevant to stronger longer-term memory with repetitive learning is novel and interesting. To the extent that these observations can be generalized to mammals, they may relate to the acute and chronic soluble Aβ oligomer-induced dysregulation of Rac/PAK/LIMK1/cofilin signaling (Zhao et al 2006., Ma et al., 2008, Gureviciene et al., and other refs) with LTP deficits and enhanced LTD (Li et al., 2009) and synapse loss (Freir et al., 2010). Conversely, memory consolidation is also impaired along with enhanced LTP and reduced LTP when PAK is selectively genetically inhibited in forebrain (Hayashi et al., 2004).
References:
Li S, Hong S, Shepardson NE, Walsh DM, Shankar GM, Selkoe D.
Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake.
Neuron. 2009 Jun 25;62(6):788-801.
PubMed.
Ma QL, Yang F, Calon F, Ubeda OJ, Hansen JE, Weisbart RH, Beech W, Frautschy SA, Cole GM.
p21-activated kinase-aberrant activation and translocation in Alzheimer disease pathogenesis.
J Biol Chem. 2008 May 16;283(20):14132-43.
PubMed.
Zhao L, Ma QL, Calon F, Harris-White ME, Yang F, Lim GP, Morihara T, Ubeda OJ, Ambegaokar S, Hansen JE, Weisbart RH, Teter B, Frautschy SA, Cole GM.
Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease.
Nat Neurosci. 2006 Feb;9(2):234-42.
PubMed.
Hayashi ML, Choi SY, Rao BS, Jung HY, Lee HK, Zhang D, Chattarji S, Kirkwood A, Tonegawa S.
Altered cortical synaptic morphology and impaired memory consolidation in forebrain- specific dominant-negative PAK transgenic mice.
Neuron. 2004 Jun 10;42(5):773-87.
PubMed.
Gureviciene I, Ikonen S, Gurevicius K, Sarkaki A, van Groen T, Pussinen R, Ylinen A, Tanila H.
Normal induction but accelerated decay of LTP in APP + PS1 transgenic mice.
Neurobiol Dis. 2004 Mar;15(2):188-95.
PubMed.
Balducci C, Beeg M, Stravalaci M, Bastone A, Sclip A, Biasini E, Tapella L, Colombo L, Manzoni C, Borsello T, Chiesa R, Gobbi M, Salmona M, Forloni G.
Synthetic amyloid-beta oligomers impair long-term memory independently of cellular prion protein.
Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2295-300.
PubMed.
Freir DB, Fedriani R, Scully D, Smith IM, Selkoe DJ, Walsh DM, Regan CM.
Abeta oligomers inhibit synapse remodelling necessary for memory consolidation.
Neurobiol Aging. 2010 Jan 22;
PubMed.
Comments
UCLA/VA
This fly paper catches genetic evidence that Rac inhibition slows memory decay, constitutively increased Rac activation accelerates memory decay, and that cofilin hyperactivation gives rise to the same phenotype as seen with Rac inhibition. The authors conclude that the “Rac-regulated PAK/LIMK/cofilin pathway might be critical in influencing memory decay.” The specificity for Rac activation defects in an active forgetting process relevant to stronger longer-term memory with repetitive learning is novel and interesting. To the extent that these observations can be generalized to mammals, they may relate to the acute and chronic soluble Aβ oligomer-induced dysregulation of Rac/PAK/LIMK1/cofilin signaling (Zhao et al 2006., Ma et al., 2008, Gureviciene et al., and other refs) with LTP deficits and enhanced LTD (Li et al., 2009) and synapse loss (Freir et al., 2010). Conversely, memory consolidation is also impaired along with enhanced LTP and reduced LTP when PAK is selectively genetically inhibited in forebrain (Hayashi et al., 2004).
References:
Li S, Hong S, Shepardson NE, Walsh DM, Shankar GM, Selkoe D. Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron. 2009 Jun 25;62(6):788-801. PubMed.
Ma QL, Yang F, Calon F, Ubeda OJ, Hansen JE, Weisbart RH, Beech W, Frautschy SA, Cole GM. p21-activated kinase-aberrant activation and translocation in Alzheimer disease pathogenesis. J Biol Chem. 2008 May 16;283(20):14132-43. PubMed.
Zhao L, Ma QL, Calon F, Harris-White ME, Yang F, Lim GP, Morihara T, Ubeda OJ, Ambegaokar S, Hansen JE, Weisbart RH, Teter B, Frautschy SA, Cole GM. Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease. Nat Neurosci. 2006 Feb;9(2):234-42. PubMed.
Hayashi ML, Choi SY, Rao BS, Jung HY, Lee HK, Zhang D, Chattarji S, Kirkwood A, Tonegawa S. Altered cortical synaptic morphology and impaired memory consolidation in forebrain- specific dominant-negative PAK transgenic mice. Neuron. 2004 Jun 10;42(5):773-87. PubMed.
Gureviciene I, Ikonen S, Gurevicius K, Sarkaki A, van Groen T, Pussinen R, Ylinen A, Tanila H. Normal induction but accelerated decay of LTP in APP + PS1 transgenic mice. Neurobiol Dis. 2004 Mar;15(2):188-95. PubMed.
Balducci C, Beeg M, Stravalaci M, Bastone A, Sclip A, Biasini E, Tapella L, Colombo L, Manzoni C, Borsello T, Chiesa R, Gobbi M, Salmona M, Forloni G. Synthetic amyloid-beta oligomers impair long-term memory independently of cellular prion protein. Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2295-300. PubMed.
Freir DB, Fedriani R, Scully D, Smith IM, Selkoe DJ, Walsh DM, Regan CM. Abeta oligomers inhibit synapse remodelling necessary for memory consolidation. Neurobiol Aging. 2010 Jan 22; PubMed.
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