Inhibition of Rac1-dependent forgetting alleviates memory deficits in animal models of Alzheimer’s disease

Abstract

Accelerated forgetting has been identified as a feature of Alzheimer’s disease (AD), but the therapeutic efficacy of the manipulation of biological mechanisms of forgetting has not been assessed in AD animal models. Ras-related C3 botulinum toxin substrate 1 (Rac1), a small GTPase, has been shown to regulate active forgetting in Drosophila and mice. Here, we showed that Rac1 activity is aberrantly elevated in the hippocampal tissues of AD patients and AD animal models. Moreover, amyloid-beta 42 could induce Rac1 activation in cultured cells. The elevation of Rac1 activity not only accelerated 6-hour spatial memory decay in 3-month-old APP/PS1 mice, but also significantly contributed to severe memory loss in aged APP/PS1 mice. A similar age-dependent Rac1 activity-based memory loss was also observed in an AD fly model. Moreover, inhibition of Rac1 activity could ameliorate cognitive defects and synaptic plasticity in AD animal models. Finally, two novel compounds, identified through behavioral screening of a randomly selected pool of brain permeable small molecules for their positive effect in rescuing memory loss in both fly and mouse models, were found to be capable of inhibiting Rac1 activity. Thus, multiple lines of evidence corroborate in supporting the idea that inhibition of Rac1 activity is effective for treating AD-related memory loss.

Keywords

Alzheimer’s disease / Rac1 / forgetting / memory loss / hippocampus

References

[1] Ballatore C, Lee VMY, Trojanowski JQ (2007) Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 8:663–672

[2] Bamburg JR (1999) Proteins of the ADF/cofilin family: esstential regulators of actin dynamics. Annu Dev Biol 15:185–230

[3] Baranczewski P, Stañczak A, Sundberg K, Wallin Å, Jansson J, Garberg P, Postlind H (2006) Introduction to in vitro estimation of metabolic stability and drug interactions of new chemical entities in drug discovery and development. Pharmacol Rep 58:453–472

[4] Barnes NY, Shi J, Yajima H, Thinakaran G, Parent AT (2008) Steady-state increase of cAMP-response element binding protein, Rac, and PAK signaling in presenilin-deficient neurons. J Neurochem 104:1637–1648

[5] Bliss TV, Collingridge GL (1993) A synaptic model of memory: longterm potentiation in the hippocampus. Nature 361:31–39

[6] Borin M, Saraceno C, Catania M, Lorenzetto E, Pontelli V, Paterlini A, Fostinelli S, Avesani A, Di Fede G, Zanusso G (2018) Rac1 activation links tau hyperphosphorylation and Aß dysmetabolism in Alzheimer’s disease. Acta Neuropathol Commun 6:1–17

[7] Brogden RN, Sorkin EM (1990) Properties, and therapeutic potential in hypertension and peripheral vascular disease a review of its pharmacodynamic and pharmacokinetic ketanserin. Drugs 40:903–949

[8] Cervantes-Sandoval I, Chakraborty M, MacMullen C, Davis RL (2016) Scribble scaffolds a signalosome for active forgetting. Neuron 90:1230–1242

[9] Davis RL, Zhong Y (2017) Perspective the biology of forgetting—a perspective. Neuron 95:490–503

[10] Edwards DC, Sanders LC, Bokoch GM, Gill GN (1999) Activation of LIM-kinase by Pak1 couples Rac / Cdc42 GTPase signalling to actin cytoskeletal dynamics. Nat Cell Biol 1:253–259

[11] Etienne-Manneville S, Hall A (2002) Rho GTPases in cell biology. Nature 420:629–635

[12] Firat-Karalar EN, Welch MD (2011) New mechanisms and functions of actin nucleation. Curr Opin Cell Biol 23:4–13

[13] Gao Q, Yao W, Wang J, Yang T, Liu C, Tao Y, Chen Y, Liu X, Ma L (2015) Post-training activation of Rac1 in the basolateral amygdala is required for the formation of both short-term and long-term auditory fear memory. Front Mol Neurosci 8:1–10

[14] Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356

[15] Hart RP, Kwentus JA, Harkins SW, Taylor JR (1988) Rate of forgetting in mild Alzheimer’s-type dementia. Brain Cogn 7:31–38

[16] Hayashi-takagi A, Nakamura M, Shirai F, Wu Y, Loshbaugh AL, Kuhlman B, Hahn KM, Kasai H, Hill C, Hill C (2015) Labelling and optical erasure of synaptic memory traces in the motor cortex. Nature 525:333–338

[17] Huang TY, Michael S, Xu T, Sarkeshik A, Moresco JJ, Yates JR, Masliah E, Bokoch GM, DerMardirossian C (2013) A novel Rac1 GAP splice variant relays poly-Ub accumulation signals to mediate Rac1 inactivation. Mol Biol Cell 24:194–209

[18] Iijima K, Liu H-P, Chiang A-S, Hearn SA, Konsolaki M, Zhong Y (2004) Dissecting the pathological effects of human A 40 and A 42 in drosophila: a potential model for Alzheimer’s disease. Proc Natl Acad Sci 101:6623–6628

[19] Kim T, Vidal GS, Djurisic M, William CM, Birnbaum ME, Garcia KC, Hyman BT, Shatz CJ (2013) Human LilrB2 is a β-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer’s model. Science 341:1399–1404

[20] Kitamura T, Ogawa SK, Roy DS, Okuyama T, Morrissey MD, Smith LM, Redondo RL, Tonegawa S (2017) Engrams and circuits crucial for systems consolidation of a memory. Science 356:73–78

[21] Klyubin I, Walsh DM, Lemere CA, Cullen WK, Shankar GM, Betts V, Spooner ET, Jiang L, Anwyl R, Selkoe DJ (2005) Amyloid β protein immunotherapy neutralizes Aβ oligomers that disrupt synaptic plasticity in vivo. Nat Med 11:556–561

[22] Liu Y, Du S, Lv L, Lei B, Shi W, Tang Y, Wang L, Zhong Y (2016) Hippocampal activation of Rac1 regulates the forgetting of object recognition memory. Curr Biol 26:2351–2357

[23] Liu Y, Lv L, Wang L, Zhong Y (2018) Social isolation induces Rac1-dependent forgetting of social memory. Cell Rep 25:288–295

[24] Ma MW, Wang J, Zhang Q, Wang R, Dhandapani KM, Vadlamudi RK, Brann DW (2017) NADPH oxidase in brain injury and neurodegenerative disorders. Mol Neurodegener 12:7

[25] Manterola L, Hernando-Rodríguez M, Ruiz A, Apraiz A, Arrizabalaga O, Vellón L, Alberdi E, Cavaliere F, Lacerda HM, Jimenez S (2013) 1-42 β-amyloid peptide requires PDK1/nPKC/Rac 1 pathway to induce neuronal death. Transl Psychiatry 3:1–11

[26] Mendoza-Naranjo A, Gonzalez-Billault C, Maccioni RB (2007) Abeta1-42 stimulates actin polymerization in hippocampal neurons through Rac1 and Cdc42 Rho GTPases. J Cell Sci 120:279–288

[27] Montalvo-Ortiz BL, Castillo-Pichardo L, Hernández E, Humphries-Bickley T, De La Mota-Peynado A, Cubano LA, Vlaar CP, Dharmawardhane S (2012) Characterization of EHop-016, novel small molecule inhibitor of Rac GTPase. J Biol Chem 287:13228–13238

[28] Mufson E, Mahady L, Waters D, Counts S, Perez S, DeKosky S, Ginsberg S, Ikonomovic DM, Scheff S, Binder L (2015) Hippocampal plasticity during the progression of Alzheimer’s disease. Neuroscience 309:51–67

[29] Nalbantoglu J, Tirado-Santiago G, Lahsaïni A, Poirier J, Goncalves O, Verge G, Momoli F, Welner SA, Massicotte G, Julien JP (1997) Impaired learning and LTP in mice expressing the carboxy terminus of the Alzheimer amyloid precursor protein. Nature 387:500–505

[30] Petratos S, Li QX, George AJ, Hou X, Kerr ML, Unabia SE, Hatzinisiriou I, Maksel D, Aguilar MI, Small DH (2008) The β-amyloid protein of Alzheimer’s disease increases neuronal CRMP-2 phosphorylation by a Rho-GTP mechanism. Brain 131:90–108

[31] Pollard TD, Borisy GG, Haven N (2003) Cellular motility driven by assembly and disassembly of actin filaments. Cell 112:453–465

[32] Reitz C, Brayne C, Mayeux R (2011) Epidemiology of Alzheimer disease. Nat Rev Neurol 7:137–152

[33] Rouiller I, Xu X-P, Amann KJ, Egile C, Nickell S, Nicastro D, Li R, Pollard TD, Volkmann N, Hanein D (2008) The structural basis of actin filament branching by the Arp2/3 complex. J Cell Biol 180:887–895

[34] Salmon DP, Granholm E, McCullough D, Butters N, Grant I (1989) Recognition memory span in mildly and moderately demented patients with Alzheimer’s disease. J Clin Exp Neuropsychol 11:429–443

[35] Sander EE, van Delft S, ten Klooster JP, Reid T, van der Kammen RA, Michiels F, Collard JG (1998) Matrix-dependent Tiam1/Rac signaling in epithelial cells promotes either cell-cell adhesion or cell migration and is regulated by phosphatidylinositol 3-kinase. J Cell Biol 143:1385–1398

[36] Shuai Y, Lu B, Hu Y, Wang L, Sun K, Zhong Y (2010) Forgetting is regulated through Rac activity in drosophila. Cell 140:579–589

[37] Trinchese F, Liu S, Battaglia F, Walter S, Mathews PM, Arancio O (2004) Progressive age-related development of Alzheimer-like pathology in APP/PS1 mice. Ann Neurol 55:801–814

[38] Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1:848–858

[39] Wang L, Chiang H-C, Wu W, Liang B, Xie Z, Yao X, Ma W, Du S, Zhong Y (2012) Epidermal growth factor receptor is a preferred target for treating amyloid-β-induced memory loss. Proc Natl Acad Sci USA 109:16743–16748

[40] Wang Q, Rager JD, Weinstein K, Kardos PS, Dobson GL, Li J, Hidalgo IJ (2005) Evaluation of the MDR-MDCK cell line as a permeability screen for the blood-brain barrier. Int J Pharm 288:349–359

[41] Weston PSJ, Nicholas JM, Henley SMD, Liang Y, Macpherson K, Donnachie E, Schott JM, Rossor MN, Crutch SJ, Butler CR (2018) Articles accelerated long-term forgetting in presymptomatic autosomal dominant Alzheimer ’ s disease: a crosssectional study. Lancet 1:123–132

[42] Zhang W, Bai M, Xi Y, Hao J, Liu L, Mao N, Su C, Miao J, Li Z (2012) Early memory deficits precede plaque deposition in APPswe/PS1dE9 mice: involvement of oxidative stress and cholinergic dysfunction. Free Radic Biol Med 52:1443–1452

[43] Zhao L, Ma QL, Calon F, Harris-White ME, Yang F, Lim GP, Morihara T, Ubeda OJ, Ambegaokar S, Hansen JE (2006) Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease. Nat Neurosci 9:234–242

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