Inhibiting BACE1 to Reverse Synaptic Dysfunctions in Alzheimer's Disease

Overview

Journal Neurosci Biobehav Rev

Specialties Neurology
Psychology
Social Sciences

Date 2016 Apr 6

PMID 27044452

Citations 35

Authors

Riqiang Yan

Qingyuan Fan

John Zhou

Robert Vassar

Affiliations

Soon will be listed here.

Abstract

Over the past two decades, many studies have identified significant contributions of toxic β-amyloid peptides (Aβ) to the etiology of Alzheimer's disease (AD), which is the most common age-dependent neurodegenerative disease. AD is also recognized as a disease of synaptic failure. Aβ, generated by sequential proteolytic cleavages of amyloid precursor protein (APP) by BACE1 and γ-secretase, is one of major culprits that cause this failure. In this review, we summarize current findings on how BACE1-cleaved APP products impact learning and memory through proteins localized on glutamatergic, GABAergic, and dopaminergic synapses. Considering the broad effects of Aβ on all three types of synapses, BACE1 inhibition emerges as a practical approach for ameliorating Aβ-mediated synaptic dysfunctions. Since BACE1 inhibitory drugs are currently in clinical trials, this review also discusses potential complications arising from BACE1 inhibition. We emphasize that the benefits of BACE1 inhibitory drugs will outweigh the concerns.

Citing Articles

Proteomic Analysis of a Rat Streptozotocin Model Shows Dysregulated Biological Pathways Implicated in Alzheimer's Disease.

da Silva E, Fischer J, Souza I, Andrade A, Souza L, Andrade M Int J Mol Sci. 2024; 25(5).

PMID: 38474019 PMC: 10931650. DOI: 10.3390/ijms25052772.

BACE1 in PV interneuron tunes hippocampal CA1 local circuits and resets priming of fear memory extinction.

Xiao X, Wang X, Zhu K, Li L, He Y, Zhang J Mol Psychiatry. 2023; 28(10):4151-4162.

PMID: 37452089 DOI: 10.1038/s41380-023-02176-y.

In silico and in vitro analyses of a novel FoxO1 agonist reducing Aβ levels via downregulation of BACE1.

Lv M, Wang H, Meng X, Shi Y, Zhang Y, Shan L CNS Neurosci Ther. 2023; 30(3):e14140.

PMID: 36892036 PMC: 10915984. DOI: 10.1111/cns.14140.

Biological Mechanism-based Neurology and Psychiatry: A BACE1/2 and Downstream Pathway Model.

Hampel H, Caruso G, Nistico R, Piccioni G, Mercuri N, Giorgi F Curr Neuropharmacol. 2021; 21(1):31-53.

PMID: 34852743 PMC: 10193755. DOI: 10.2174/1570159X19666211201095701.

MicroRNA-132-3p alleviates neuron apoptosis and impairments of learning and memory abilities in Alzheimer's disease by downregulation of HNRNPU stabilized BACE1.

Qu J, Xiong X, Hujie G, Ren J, Yan L, Ma L Cell Cycle. 2021; 20(21):2309-2320.

PMID: 34585626 PMC: 8794521. DOI: 10.1080/15384101.2021.1982507.

References

Haniu M, Denis P, Young Y, Mendiaz E, Fuller J, Hui J . Characterization of Alzheimer's beta -secretase protein BACE. A pepsin family member with unusual properties. J Biol Chem. 2000; 275(28):21099-106. DOI: 10.1074/jbc.M002095200. View

Yan R, Bienkowski M, Shuck M, Miao H, Tory M, Pauley A . Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature. 1999; 402(6761):533-7. DOI: 10.1038/990107. View

Minano-Molina A, Espana J, Martin E, Barneda-Zahonero B, Fado R, Sole M . Soluble oligomers of amyloid-β peptide disrupt membrane trafficking of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor contributing to early synapse dysfunction. J Biol Chem. 2011; 286(31):27311-21. PMC: 3149325. DOI: 10.1074/jbc.M111.227504. View

Thomas G, Huganir R . MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci. 2004; 5(3):173-83. DOI: 10.1038/nrn1346. View

Finan G, Okada H, Kim T . BACE1 retrograde trafficking is uniquely regulated by the cytoplasmic domain of sortilin. J Biol Chem. 2011; 286(14):12602-16. PMC: 3069461. DOI: 10.1074/jbc.M110.170217. View

Kemppainen N, Laine M, Laakso M, Kaasinen V, Nagren K, Vahlberg T . Hippocampal dopamine D2 receptors correlate with memory functions in Alzheimer's disease. Eur J Neurosci. 2003; 18(1):149-54. DOI: 10.1046/j.1460-9568.2003.02716.x. View

Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A . Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature. 2000; 407(6800):48-54. DOI: 10.1038/35024009. View

He W, Hu J, Xia Y, Yan R . β-site amyloid precursor protein cleaving enzyme 1(BACE1) regulates Notch signaling by controlling the cleavage of Jagged 1 (Jag1) and Jagged 2 (Jag2) proteins. J Biol Chem. 2014; 289(30):20630-7. PMC: 4110275. DOI: 10.1074/jbc.M114.579862. View

Zhou L, Barao S, Laga M, Bockstael K, Borgers M, Gijsen H . The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo. J Biol Chem. 2012; 287(31):25927-40. PMC: 3406677. DOI: 10.1074/jbc.M112.377465. View

10.

Hu X, He W, Luo X, Tsubota K, Yan R . BACE1 regulates hippocampal astrogenesis via the Jagged1-Notch pathway. Cell Rep. 2013; 4(1):40-9. PMC: 3740554. DOI: 10.1016/j.celrep.2013.06.005. View

11.

Sankaranarayanan S, Price E, Wu G, Crouthamel M, Shi X, Tugusheva K . In vivo beta-secretase 1 inhibition leads to brain Abeta lowering and increased alpha-secretase processing of amyloid precursor protein without effect on neuregulin-1. J Pharmacol Exp Ther. 2007; 324(3):957-69. DOI: 10.1124/jpet.107.130039. View

12.

Ables J, Breunig J, Eisch A, Rakic P . Not(ch) just development: Notch signalling in the adult brain. Nat Rev Neurosci. 2011; 12(5):269-83. PMC: 3159580. DOI: 10.1038/nrn3024. View

13.

Fitzgerald M, Chan J, Mackie K, Lupica C, Pickel V . Altered dendritic distribution of dopamine D2 receptors and reduction in mitochondrial number in parvalbumin-containing interneurons in the medial prefrontal cortex of cannabinoid-1 (CB1) receptor knockout mice. J Comp Neurol. 2012; 520(17):4013-31. PMC: 3685630. DOI: 10.1002/cne.23141. View

14.

Allinson T, Parkin E, Condon T, Schwager S, Sturrock E, Turner A . The role of ADAM10 and ADAM17 in the ectodomain shedding of angiotensin converting enzyme and the amyloid precursor protein. Eur J Biochem. 2004; 271(12):2539-47. DOI: 10.1111/j.1432-1033.2004.04184.x. View

15.

Kuhn P, Koroniak K, Hogl S, Colombo A, Zeitschel U, Willem M . Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons. EMBO J. 2012; 31(14):3157-68. PMC: 3400020. DOI: 10.1038/emboj.2012.173. View

16.

Kessels H, Nabavi S, Malinow R . Metabotropic NMDA receptor function is required for β-amyloid-induced synaptic depression. Proc Natl Acad Sci U S A. 2013; 110(10):4033-8. PMC: 3593880. DOI: 10.1073/pnas.1219605110. View

17.

Araki W, Oda A, Motoki K, Hattori K, Itoh M, Yuasa S . Reduction of β-amyloid accumulation by reticulon 3 in transgenic mice. Curr Alzheimer Res. 2012; 10(2):135-42. DOI: 10.2174/1567205011310020003. View

18.

Sinha S, Anderson J, Barbour R, Basi G, Caccavello R, Davis D . Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature. 1999; 402(6761):537-40. DOI: 10.1038/990114. View

19.

Yuen E, Zhong P, Yan Z . Homeostatic regulation of glutamatergic transmission by dopamine D4 receptors. Proc Natl Acad Sci U S A. 2010; 107(51):22308-13. PMC: 3009820. DOI: 10.1073/pnas.1010025108. View

20.

Tesco G, Koh Y, Kang E, Cameron A, Das S, Sena-Esteves M . Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity. Neuron. 2007; 54(5):721-37. PMC: 1973166. DOI: 10.1016/j.neuron.2007.05.012. View