1. Tsinghua-Peking Center for Life Science, IDG/McGovern Institutes for Brain Research, MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua University, Beijing 100084, China 2. Life Science Division, Graduate school at Shenzhen, Tsinghua University, Shenzhen 518055, China 3. JoeKai Biotech. LLC, LianQiang International Building, Yongfeng Base, Beijing 100084, China 4. Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, China 5. Key Lab of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China 6. Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Human Anatomy, Histology and Embryology, Neuroscience Center, Joint Laboratory of Anesthesia and Pain, School of Basic Medicine, Peking Union Medical College, Beijing 100005, China
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.
C Ballatore, VMY Lee, JQ Trojanowski (2007) Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 8:663–672 https://doi.org/10.1038/nrn2194
P Baranczewski, A Stañczak, K Sundberg, Å Wallin, J Jansson, P Garberg, H Postlind (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
NY Barnes, J Shi, H Yajima, G Thinakaran, AT Parent (2008) Steady-state increase of cAMP-response element binding protein, Rac, and PAK signaling in presenilin-deficient neurons. J Neurochem 104:1637–1648 https://doi.org/10.1111/j.1471-4159.2007.05102.x
5
TV Bliss, GL Collingridge (1993) A synaptic model of memory: longterm potentiation in the hippocampus. Nature 361:31–39 https://doi.org/10.1038/361031a0
6
M Borin, C Saraceno, M Catania, E Lorenzetto, V Pontelli, A Paterlini, S Fostinelli, A Avesani, G Di Fede, G Zanussoet al. (2018) Rac1 activation links tau hyperphosphorylation and Aß dysmetabolism in Alzheimer’s disease. Acta Neuropathol Commun 6:1–17 https://doi.org/10.1186/s40478-018-0567-4
7
RN Brogden, EM Sorkin (1990) Properties, and therapeutic potential in hypertension and peripheral vascular disease a review of its pharmacodynamic and pharmacokinetic ketanserin. Drugs 40:903–949 https://doi.org/10.2165/00003495-199040060-00010
8
I Cervantes-Sandoval, M Chakraborty, C MacMullen, RL Davis (2016) Scribble scaffolds a signalosome for active forgetting. Neuron 90:1230–1242 https://doi.org/10.1016/j.neuron.2016.05.010
Q Gao, W Yao, J Wang, T Yang, C Liu, Y Tao, Y Chen, X Liu, L Ma (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 https://doi.org/10.3389/fnmol.2015.00065
14
J Hardy, DJ Selkoe (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356 https://doi.org/10.1126/science.1072994
A Hayashi-takagi, M Nakamura, F Shirai, Y Wu, AL Loshbaugh, B Kuhlman, KM Hahn, H Kasai, C Hill, C Hillet al. (2015) Labelling and optical erasure of synaptic memory traces in the motor cortex. Nature 525:333–338 https://doi.org/10.1038/nature15257
17
TY Huang, S Michael, T Xu, A Sarkeshik, JJ Moresco, JR Yates, E Masliah, GM Bokoch, C DerMardirossian (2013) A novel Rac1 GAP splice variant relays poly-Ub accumulation signals to mediate Rac1 inactivation. Mol Biol Cell 24:194–209 https://doi.org/10.1091/mbc.e12-07-0565
18
K Iijima, H-P Liu, A-S Chiang, SA Hearn, M Konsolaki, Y Zhong (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 https://doi.org/10.1073/pnas.0400895101
19
T Kim, GS Vidal, M Djurisic, CM William, ME Birnbaum, KC Garcia, BT Hyman, CJ Shatz (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 https://doi.org/10.1126/science.1242077
20
T Kitamura, SK Ogawa, DS Roy, T Okuyama, MD Morrissey, LM Smith, RL Redondo, S Tonegawa (2017) Engrams and circuits crucial for systems consolidation of a memory. Science 356:73–78 https://doi.org/10.1126/science.aam6808
21
I Klyubin, DM Walsh, CA Lemere, WK Cullen, GM Shankar, V Betts, ET Spooner, L Jiang, R Anwyl, DJ Selkoeet al. (2005) Amyloid β protein immunotherapy neutralizes Aβ oligomers that disrupt synaptic plasticity in vivo. Nat Med 11:556–561 https://doi.org/10.1038/nm1234
22
Y Liu, S Du, L Lv, B Lei, W Shi, Y Tang, L Wang, Y Zhong (2016) Hippocampal activation of Rac1 regulates the forgetting of object recognition memory. Curr Biol 26:2351–2357 https://doi.org/10.1016/j.cub.2016.06.056
MW Ma, J Wang, Q Zhang, R Wang, KM Dhandapani, RK Vadlamudi, DW Brann (2017) NADPH oxidase in brain injury and neurodegenerative disorders. Mol Neurodegener 12:7 https://doi.org/10.1186/s13024-017-0150-7
25
L Manterola, M Hernando-Rodríguez, A Ruiz, A Apraiz, O Arrizabalaga, L Vellón, E Alberdi, F Cavaliere, HM Lacerda, S Jimenezet al. (2013) 1-42 β-amyloid peptide requires PDK1/nPKC/Rac 1 pathway to induce neuronal death. Transl Psychiatry 3:1–11 https://doi.org/10.1038/tp.2012.147
26
A Mendoza-Naranjo, C Gonzalez-Billault, RB Maccioni (2007) Abeta1-42 stimulates actin polymerization in hippocampal neurons through Rac1 and Cdc42 Rho GTPases. J Cell Sci 120:279–288 https://doi.org/10.1242/jcs.03323
27
BL Montalvo-Ortiz, L Castillo-Pichardo, E Hernández, T Humphries-Bickley, A De La Mota-Peynado, LA Cubano, CP Vlaar, S Dharmawardhane (2012) Characterization of EHop-016, novel small molecule inhibitor of Rac GTPase. J Biol Chem 287:13228–13238 https://doi.org/10.1074/jbc.M111.334524
28
E Mufson, L Mahady, D Waters, S Counts, S Perez, S DeKosky, S Ginsberg, DM Ikonomovic, S Scheff, L Binder (2015) Hippocampal plasticity during the progression of Alzheimer’s disease. Neuroscience 309:51–67 https://doi.org/10.1016/j.neuroscience.2015.03.006
29
J Nalbantoglu, G Tirado-Santiago, A Lahsaïni, J Poirier, O Goncalves, G Verge, F Momoli, SA Welner, G Massicotte, JP Julienet al. (1997) Impaired learning and LTP in mice expressing the carboxy terminus of the Alzheimer amyloid precursor protein. Nature 387:500–505 https://doi.org/10.1038/387500a0
30
S Petratos, QX Li, AJ George, X Hou, ML Kerr, SE Unabia, I Hatzinisiriou, D Maksel, MI Aguilar, DH Small (2008) The β-amyloid protein of Alzheimer’s disease increases neuronal CRMP-2 phosphorylation by a Rho-GTP mechanism. Brain 131:90–108 https://doi.org/10.1093/brain/awm260
I Rouiller, X-P Xu, KJ Amann, C Egile, S Nickell, D Nicastro, R Li, TD Pollard, N Volkmann, D Hanein (2008) The structural basis of actin filament branching by the Arp2/3 complex. J Cell Biol 180:887–895 https://doi.org/10.1083/jcb.200709092
34
DP Salmon, E Granholm, D McCullough, N Butters, I Grant (1989) Recognition memory span in mildly and moderately demented patients with Alzheimer’s disease. J Clin Exp Neuropsychol 11:429–443 https://doi.org/10.1080/01688638908400904
35
EE Sander, S van Delft, JP ten Klooster, T Reid, RA van der Kammen, F Michiels, JG Collard (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 https://doi.org/10.1083/jcb.143.5.1385
36
Y Shuai, B Lu, Y Hu, L Wang, K Sun, Y Zhong (2010) Forgetting is regulated through Rac activity in drosophila. Cell 140:579–589 https://doi.org/10.1016/j.cell.2009.12.044
37
F Trinchese, S Liu, F Battaglia, S Walter, PM Mathews, O Arancio (2004) Progressive age-related development of Alzheimer-like pathology in APP/PS1 mice. Ann Neurol 55:801–814 https://doi.org/10.1002/ana.20101
38
CV Vorhees, MT Williams (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1:848–858 https://doi.org/10.1038/nprot.2006.116
39
L Wang, H-C Chiang, W Wu, B Liang, Z Xie, X Yao, W Ma, S Du, Y Zhong (2012) Epidermal growth factor receptor is a preferred target for treating amyloid-β-induced memory loss. Proc Natl Acad Sci USA 109:16743–16748 https://doi.org/10.1073/pnas.1208011109
40
Q Wang, JD Rager, K Weinstein, PS Kardos, GL Dobson, J Li, IJ Hidalgo (2005) Evaluation of the MDR-MDCK cell line as a permeability screen for the blood-brain barrier. Int J Pharm 288:349–359 https://doi.org/10.1016/j.ijpharm.2004.10.007
41
PSJ Weston, JM Nicholas, SMD Henley, Y Liang, K Macpherson, E Donnachie, JM Schott, MN Rossor, SJ Crutch, CR Butleret al. (2018) Articles accelerated long-term forgetting in presymptomatic autosomal dominant Alzheimer ’ s disease: a crosssectional study. Lancet 1:123–132 https://doi.org/10.1016/S1474-4422(17)30434-9
42
W Zhang, M Bai, Y Xi, J Hao, L Liu, N Mao, C Su, J Miao, Z Li (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 https://doi.org/10.1016/j.freeradbiomed.2012.01.023
43
L Zhao, QL Ma, F Calon, ME Harris-White, F Yang, GP Lim, T Morihara, OJ Ubeda, S Ambegaokar, JE Hansenet al. (2006) Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease. Nat Neurosci 9:234–242 https://doi.org/10.1038/nn1630
