BACE1 Function and Inhibition: Implications of Intervention in the Amyloid Pathway of Alzheimer's Disease Pathology

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2017 Oct 14

PMID 29027981

Citations 47

Authors

Gerald Koelsch

Affiliations

Soon will be listed here.

Abstract

Alzheimer's disease (AD) is a fatal progressive neurodegenerative disorder characterized by increasing loss in memory, cognition, and function of daily living. Among the many pathologic events observed in the progression of AD, changes in amyloid β peptide (Aβ) metabolism proceed fastest, and precede clinical symptoms. BACE1 (β-secretase 1) catalyzes the initial cleavage of the amyloid precursor protein to generate Aβ. Therefore inhibition of BACE1 activity could block one of the earliest pathologic events in AD. However, therapeutic BACE1 inhibition to block Aβ production may need to be balanced with possible effects that might result from diminished physiologic functions BACE1, in particular processing of substrates involved in neuronal function of the brain and periphery. Potentials for beneficial or consequential effects resulting from pharmacologic inhibition of BACE1 are reviewed in context of ongoing clinical trials testing the effect of BACE1 candidate inhibitor drugs in AD populations.

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References

Cebers G, Alexander R, Budd Haeberlein S, Han D, Goldwater R, Ereshefsky L . AZD3293: Pharmacokinetic and Pharmacodynamic Effects in Healthy Subjects and Patients with Alzheimer's Disease. J Alzheimers Dis. 2016; 55(3):1039-1053. DOI: 10.3233/JAD-160701. 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

Yan R . Stepping closer to treating Alzheimer's disease patients with BACE1 inhibitor drugs. Transl Neurodegener. 2016; 5:13. PMC: 4944430. DOI: 10.1186/s40035-016-0061-5. View

Ko M, Puglielli L . Two endoplasmic reticulum (ER)/ER Golgi intermediate compartment-based lysine acetyltransferases post-translationally regulate BACE1 levels. J Biol Chem. 2008; 284(4):2482-92. PMC: 2629114. DOI: 10.1074/jbc.M804901200. View

Ferreira S, Lourenco M, Oliveira M, De Felice F . Soluble amyloid-β oligomers as synaptotoxins leading to cognitive impairment in Alzheimer's disease. Front Cell Neurosci. 2015; 9:191. PMC: 4443025. DOI: 10.3389/fncel.2015.00191. View

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

Kinoshita A, Fukumoto H, Shah T, Whelan C, Irizarry M, Hyman B . Demonstration by FRET of BACE interaction with the amyloid precursor protein at the cell surface and in early endosomes. J Cell Sci. 2003; 116(Pt 16):3339-46. DOI: 10.1242/jcs.00643. View

Kobayashi D, Zeller M, Cole T, Buttini M, McConlogue L, Sinha S . BACE1 gene deletion: impact on behavioral function in a model of Alzheimer's disease. Neurobiol Aging. 2007; 29(6):861-73. DOI: 10.1016/j.neurobiolaging.2007.01.002. View

Harrison S, Harper A, Hawkins J, Duddy G, Grau E, Pugh P . BACE1 (beta-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes. Mol Cell Neurosci. 2003; 24(3):646-55. DOI: 10.1016/s1044-7431(03)00227-6. View

10.

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

11.

Hu X, Zhou X, He W, Yang J, Xiong W, Wong P . BACE1 deficiency causes altered neuronal activity and neurodegeneration. J Neurosci. 2010; 30(26):8819-29. PMC: 2902368. DOI: 10.1523/JNEUROSCI.1334-10.2010. View

12.

Kokawa A, Ishihara S, Fujiwara H, Nobuhara M, Iwata M, Ihara Y . The A673T mutation in the amyloid precursor protein reduces the production of β-amyloid protein from its β-carboxyl terminal fragment in cells. Acta Neuropathol Commun. 2015; 3:66. PMC: 4632685. DOI: 10.1186/s40478-015-0247-6. View

13.

Ries M, Sastre M . Mechanisms of Aβ Clearance and Degradation by Glial Cells. Front Aging Neurosci. 2016; 8:160. PMC: 4932097. DOI: 10.3389/fnagi.2016.00160. View

14.

Martiskainen H, Herukka S, Stancakova A, Paananen J, Soininen H, Kuusisto J . Decreased plasma β-amyloid in the Alzheimer's disease APP A673T variant carriers. Ann Neurol. 2017; 82(1):128-132. DOI: 10.1002/ana.24969. View

15.

Hessler S, Zheng F, Hartmann S, Rittger A, Lehnert S, Volkel M . β-Secretase BACE1 regulates hippocampal and reconstituted M-currents in a β-subunit-like fashion. J Neurosci. 2015; 35(8):3298-311. PMC: 6605557. DOI: 10.1523/JNEUROSCI.3127-14.2015. View

16.

Hughes J, Rees S, Kalindjian S, Philpott K . Principles of early drug discovery. Br J Pharmacol. 2010; 162(6):1239-49. PMC: 3058157. DOI: 10.1111/j.1476-5381.2010.01127.x. View

17.

Zhang X, Zhou K, Wang R, Cui J, Lipton S, Liao F . Hypoxia-inducible factor 1alpha (HIF-1alpha)-mediated hypoxia increases BACE1 expression and beta-amyloid generation. J Biol Chem. 2007; 282(15):10873-80. DOI: 10.1074/jbc.M608856200. View

18.

van Bebber F, Hruscha A, Willem M, Schmid B, Haass C . Loss of Bace2 in zebrafish affects melanocyte migration and is distinct from Bace1 knock out phenotypes. J Neurochem. 2013; 127(4):471-81. DOI: 10.1111/jnc.12198. View

19.

Koritzinsky M, Levitin F, van den Beucken T, Rumantir R, Harding N, Chu K . Two phases of disulfide bond formation have differing requirements for oxygen. J Cell Biol. 2013; 203(4):615-27. PMC: 3840938. DOI: 10.1083/jcb.201307185. View

20.

Walsh D, Selkoe D . A beta oligomers - a decade of discovery. J Neurochem. 2007; 101(5):1172-84. DOI: 10.1111/j.1471-4159.2006.04426.x. View