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Combination strategy employing BACE1 inhibitor and memantine to boost cognitive benefits in Alzheimer’s disease therapy

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Abstract

Rationale

The β-secretase BACE1 initiates amyloid-β (Aβ) generation and represents a long-standing prime therapeutic target for the treatment of Alzheimer’s disease (AD). However, BACE1 inhibitors tested to date in clinical trials have yielded no beneficial outcomes. In fact, prior BACE1 inhibitor trials targeted at ~ 50–90% Aβ reductions in symptomatic or prodromal AD stages have ended in the discontinuation due to futility and/or side effects, including cognitive worsening rather than expected improvement at the highest dose.

Objectives

We tested whether a combination strategy with the selective BACE1 inhibitor GRL-8234 and the FDA-approved symptomatic drug memantine may provide synergistic cognitive benefits within their safe dose range.

Methods

The drug effects were evaluated in the advanced symptomatic stage of 5XFAD mice that developed extensive cerebral Aβ deposition.

Results

Chronic combination treatment with 33.4-mg/kg GRL-8234 and 10-mg/kg memantine, but not either drug alone, rescued cognitive deficits in 5XFAD mice at 12 months of age (the endpoint after 60-day drug treatment), as assessed by the contextual fear conditioning, spontaneous alternation Y-maze and nest building tasks. Intact baseline performances of wild-type control mice on three cognitive paradigms demonstrated that combination treatment did not augment potential cognitive side effects of individual drugs. Biochemical and immunohistochemical examination showed that combination treatment did not synergistically reduce the β-amyloidogenic processing of amyloid precursor protein or Aβ levels in 5XFAD mouse brains.

Conclusions

A combination strategy with BACE1 inhibitors and memantine may be able to increase the effectiveness of individual drugs within their safe dose range in AD therapy.

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Data availability

Data will be made available upon reasonable request to the corresponding author.

References

  • Alam S, Lingenfelter KS, Bender AM, Lindsley CW (2017) Classics in chemical neuroscience: memantine. ACS Chem Neurosci 8:1823–1829

    Article  CAS  PubMed  Google Scholar 

  • Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade E, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Schofield PR, Sperling RA, Salloway S, Morris JC (2012) Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 367:795–804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bazzari FH, Bazzari AH (2022) BACE1 inhibitors for Alzheimer’s disease: the past, present and any future? Molecules 27:8823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blume T, Filser S, Jaworska A, Blain JF, Koenig G, Moschke K, Lichtenthaler SF, Herms J (2018) BACE1 inhibitor MK-8931 alters formation but not stability of dendritic spines. Front Aging Neurosci 10:229

    Article  PubMed  PubMed Central  Google Scholar 

  • Chang WP, Huang X, Downs D, Cirrito JR, Koelsch G, Holtzman DM, Ghosh AK, Tang J (2011) β-Secretase inhibitor GRL-8234 rescues age-related cognitive decline in APP transgenic mice. FASEB J 25:775–784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chow VW, Savonenko AV, Melnikova T, Kim H, Price DL, Li T, Wong PC (2010) Modeling an anti-amyloid combination therapy for Alzheimer’s disease. Sci Transl Med 2:13ra11

    Article  Google Scholar 

  • Deacon RM (2006) Assessing nest building in mice. Nat Protoc 1:1117–1119

    Article  PubMed  Google Scholar 

  • Devi L, Ohno M (2010) Phospho-eIF2α level is important for determining abilities of BACE1 reduction to rescue cholinergic neurodegeneration and memory defects in 5XFAD mice. PLoS One 5:e12974

    Article  PubMed  PubMed Central  Google Scholar 

  • Devi L, Ohno M (2012) Mitochondrial dysfunction and accumulation of the β-secretase-cleaved C-terminal fragment of APP in Alzheimer’s disease transgenic mice. Neurobiol Dis 45:417–424

    Article  CAS  PubMed  Google Scholar 

  • Devi L, Ohno M (2013) Mechanisms that lessen benefits of β-secretase reduction in a mouse model of Alzheimer’s disease. Transl Psychiatry 3:e284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Devi L, Ohno M (2015a) TrkB reduction exacerbates Alzheimer’s disease-like signaling aberrations and memory deficits without affecting β-amyloidosis in 5XFAD mice. Transl Psychiatry 5:e562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Devi L, Ohno M (2015b) A combination Alzheimer’s therapy targeting BACE1 and neprilysin in 5XFAD transgenic mice. Mol Brain 8:19

    Article  PubMed  PubMed Central  Google Scholar 

  • Devi L, Ohno M (2016) Cognitive benefits of memantine in Alzheimer’s 5XFAD model mice decline during advanced disease stages. Pharmacol Biochem Behav 144:60–66

    Article  CAS  PubMed  Google Scholar 

  • Devi L, Tang J, Ohno M (2015) Beneficial effects of the β-secretase inhibitor GRL-8234 in 5XFAD Alzheimer’s transgenic mice lessen during disease progression. Curr Alzheimer Res 12:13–21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dong H, Csernansky CA, Martin MV, Bertchume A, Vallera D, Csernansky JG (2005) Acetylcholinesterase inhibitors ameliorate behavioral deficits in the Tg2576 mouse model of Alzheimer’s disease. Psychopharmacology 181:145–152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ferreira ST, Klein WL (2011) The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease. Neurobiol Learn Mem 96:529–543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Figueiredo CP, Clarke JR, Ledo JH, Ribeiro FC, Costa CV, Melo HM, Mota-Sales AP, Saraiva LM, Klein WL, Sebollela A, De Felice FG, Ferreira ST (2013) Memantine rescues transient cognitive impairment caused by high-molecular-weight Aβ oligomers but not the persistent impairment induced by low-molecular-weight oligomers. J Neurosci 33:9626–9634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Filser S, Ovsepian SV, Masana M, Blazquez-Llorca L, Brandt Elvang A, Volbracht C, Muller MB, Jung CK, Herms J (2015) Pharmacological inhibition of BACE1 impairs synaptic plasticity and cognitive functions. Biol Psychiatry 77:729–739

    Article  CAS  PubMed  Google Scholar 

  • Folch J, Busquets O, Ettcheto M, Sánchez-López E, Castro-Torres RD, Verdaguer E, Garcia ML, Olloquequi J, Casadesús G, Beas-Zarate C, Pelegri C, Vilaplana J, Auladell C, Camins A (2018) Memantine for the treatment of dementia: a review on its current and future applications. J Alzheimers Dis 62:1223–1240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Franklin KBJ, Paxinos G (2008) The mouse brain in stereotaxic coordinates. Academic Press, New York

    Google Scholar 

  • Ghosh AK, Kumaragurubaran N, Hong L, Kulkarni S, Xu X, Miller HB, Reddy DS, Weerasena V, Turner R, Chang W, Koelsch G, Tang J (2008) Potent memapsin 2 (β-secretase) inhibitors: design, synthesis, protein-ligand X-ray structure, and in vivo evaluation. Bioorg Med Chem Lett 18:1031–1036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide. Nat Rev Mol Cell Biol 8:101–112

    Article  CAS  PubMed  Google Scholar 

  • Hampel H, Hardy J, Blennow K, Chen C, Perry G, Kim SH, Villemagne VL, Aisen P, Vendruscolo M, Iwatsubo T, Masters CL, Cho M, Lannfelt L, Cummings JL, Vergallo A (2021) The amyloid-β pathway in Alzheimer’s disease. Mol Psychiatry 26:5481–5503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Imbimbo BP, Watling M (2019) Investigational BACE inhibitors for the treatment of Alzheimer’s disease. Expert Opin Investig Drugs 28:967–975

    Article  CAS  PubMed  Google Scholar 

  • Ito K, Tatebe T, Suzuki K, Hirayama T, Hayakawa M, Kubo H, Tomita T, Makino M (2017) Memantine reduces the production of amyloid-β peptides through modulation of amyloid precursor protein trafficking. Eur J Pharmacol 798:16–25

    Article  CAS  PubMed  Google Scholar 

  • Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D, Maloney J, Hoyte K, Gustafson A, Liu Y, Lu Y, Bhangale T, Graham RR, Huttenlocher J, Bjornsdottir G, Andreassen OA, Jonsson EG, Palotie A, Behrens TW, Magnusson OT, Kong A, Thorsteinsdottir U, Watts RJ, Stefansson K (2012) A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 488:96–99

    Article  CAS  PubMed  Google Scholar 

  • Kimura R, Ohno M (2009) Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model. Neurobiol Dis 33:229–235

    Article  CAS  PubMed  Google Scholar 

  • Kimura R, Devi L, Ohno M (2010) Partial reduction of BACE1 improves synaptic plasticity, recent and remote memories in Alzheimer’s disease transgenic mice. J Neurochem 113:248–261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laird FM, Cai H, Savonenko AV, Farah MH, He K, Melnikova T, Wen H, Chiang HC, Xu G, Koliatsos VE, Borchelt DR, Price DL, Lee HK, Wong PC (2005) BACE1, a major determinant of selective vulnerability of the brain to amyloid-β amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci 25:11693–11709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Larson ME, Lesné SE (2012) Soluble Aβ oligomer production and toxicity. J Neurochem 120(Suppl 1):125–139

    Article  CAS  PubMed  Google Scholar 

  • Martiskainen H, Herukka SK, Stančáková A, Paananen J, Soininen H, Kuusisto J, Laakso M, Hiltunen M (2017) Decreased plasma β-amyloid in the Alzheimer’s disease APP A673T variant carriers. Ann Neurol 82:128–132

    Article  CAS  PubMed  Google Scholar 

  • McDade E, Voytyuk I, Aisen P, Bateman RJ, Carrillo MC, De Strooper B, Haass C, Reiman EM, Sperling R, Tariot PN, Yan R, Masters CL, Vassar R, Lichtenthaler SF (2021) The case for low-level BACE1 inhibition for the prevention of Alzheimer disease. Nat Rev Neurol 17:703–714

    Article  PubMed  Google Scholar 

  • Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, Berry R, Vassar R (2006) Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci 26:10129–10140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ohno M (2016) Alzheimer’s therapy targeting the β-secretase enzyme BACE1: benefits and potential limitations from the perspective of animal model studies. Brain Res Bull 126:183–198

    Article  CAS  PubMed  Google Scholar 

  • Ohno M (2021) Accelerated long-term forgetting is a BACE1 inhibitor-reversible incipient cognitive phenotype in Alzheimer’s disease model mice. Neuropsychopharmacol Rep 41:255–259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ohno M (2023) Accelerated long-term forgetting: a sensitive paradigm for detecting subtle cognitive impairment and evaluating BACE1 inhibitor efficacy in preclinical Alzheimer’s disease. Front Dement 2:1161875

    Article  Google Scholar 

  • Ohno M, Sametsky EA, Younkin LH, Oakley H, Younkin SG, Citron M, Vassar R, Disterhoft JF (2004) BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer’s disease. Neuron 41:27–33

    Article  CAS  PubMed  Google Scholar 

  • Ohno M, Chang L, Tseng W, Oakley H, Citron M, Klein WL, Vassar R, Disterhoft JF (2006) Temporal memory deficits in Alzheimer’s mouse models: rescue by genetic deletion of BACE1. Eur J Neurosci 23:251–260

    Article  PubMed  Google Scholar 

  • Ou-Yang MH, Kurz JE, Nomura T, Popovic J, Rajapaksha TW, Dong H, Contractor A, Chetkovich DM, Tourtellotte WG, Vassar R (2018) Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice. Sci Transl Med 10:eaao5620

    Article  PubMed  PubMed Central  Google Scholar 

  • Parsons MP, Raymond LA (2014) Extrasynaptic NMDA receptor involvement in central nervous system disorders. Neuron 82:279–293

    Article  CAS  PubMed  Google Scholar 

  • Peters F, Salihoglu H, Rodrigues E, Herzog E, Blume T, Filser S, Dorostkar M, Shimshek DR, Brose N, Neumann U, Herms J (2018) BACE1 inhibition more effectively suppresses initiation than progression of β-amyloid pathology. Acta Neuropathol 135:695–710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pratsch K, Unemura C, Ito M, Lichtenthaler SF, Horiguchi N, Herms J (2023) New highly selective BACE1 inhibitors and their effects on dendritic spine density in vivo. Int J Mol Sci 24:12283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rafii MS, Aisen PS (2023) Detection and treatment of Alzheimer’s disease in its preclinical stage. Nat Aging 3:520–531

    Article  PubMed  Google Scholar 

  • Ray B, Banerjee PK, Greig NH, Lahiri DK (2010) Memantine treatment decreases levels of secreted Alzheimer’s amyloid precursor protein (APP) and amyloid beta (Aβ) peptide in the human neuroblastoma cells. Neurosci Lett 470:1–5

    Article  CAS  PubMed  Google Scholar 

  • Schneider LS, Dagerman KS, Higgins JP, McShane R (2011) Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol 68:991–998

    Article  PubMed  Google Scholar 

  • Tu S, Okamoto S, Lipton SA, Xu H (2014) Oligomeric Aβ-induced synaptic dysfunction in Alzheimer’s disease. Mol Neurodegener 9:48

    Article  PubMed  PubMed Central  Google Scholar 

  • Van Dam D, Abramowski D, Staufenbiel M, De Deyn PP (2005) Symptomatic effect of donepezil, rivastigmine, galantamine and memantine on cognitive deficits in the APP23 model. Psychopharmacology 180:177–190

    Article  CAS  PubMed  Google Scholar 

  • van Marum RJ (2009) Update on the use of memantine in Alzheimer’s disease. Neuropsychiatr Dis Treat 5:237–247

    Article  PubMed  PubMed Central  Google Scholar 

  • van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, Kanekiyo M, Li D, Reyderman L, Cohen S, Froelich L, Katayama S, Sabbagh M, Vellas B, Watson D, Dhadda S, Irizarry M, Kramer LD, Iwatsubo T (2023) Lecanemab in early Alzheimer’s disease. N Engl J Med 388:9–21

    Article  PubMed  Google Scholar 

  • Vassar R (2019) Adult conditional BACE1 knockout mice exhibit axonal organization defects in the hippocampus: implications for BACE1 inhibitor clinical trials. J Prev Alzheimers Dis 6:78–84

    CAS  PubMed  Google Scholar 

  • Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, Szoeke C, Macaulay SL, Martins R, Maruff P, Ames D, Rowe CC, Masters CL, Australian Imaging Biomarkers and Lifestyle (AIBL) Research Group (2013) Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol 12:357–367

  • Yu SP, Jiang MQ, Shim SS, Pourkhodadad S, Wei L (2023) Extrasynaptic NMDA receptors in acute and chronic excitotoxicity: implications for preventive treatments of ischemic stroke and late-onset Alzheimer’s disease. Mol Neurodegener 18:43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu K, Peters F, Filser S, Herms J (2018a) Consequences of pharmacological BACE inhibition on synaptic structure and function. Biol Psychiatry 84:478–487

    Article  CAS  PubMed  Google Scholar 

  • Zhu K, Xiang X, Filser S, Marinković P, Dorostkar MM, Crux S, Neumann U, Shimshek DR, Rammes G, Haass C, Lichtenthaler SF, Gunnersen JM, Herms J (2018b) Beta-site amyloid precursor protein cleaving enzyme 1 inhibition impairs synaptic plasticity via seizure protein 6. Biol Psychiatry 83:428–437

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful to Dr. Jordan Tang (Oklahoma Medical Research Foundation, USA) for the generous donation of GRL-8234. This work was supported by the National Institutes of Health grant AG064149 (M.O.).

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  1. Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, 10962, USA

    Abu Md Mamun Tarif, Hasi Huhe & Masuo Ohno

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  1. Abu Md Mamun Tarif
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  2. Hasi Huhe
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  3. Masuo Ohno
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Correspondence to Masuo Ohno.

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Tarif, A.M.M., Huhe, H. & Ohno, M. Combination strategy employing BACE1 inhibitor and memantine to boost cognitive benefits in Alzheimer’s disease therapy. Psychopharmacology 241, 975–986 (2024). https://doi.org/10.1007/s00213-024-06525-9

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