Partial BACE1 reduction in a Down syndrome mouse model blocks Alzheimer-related endosomal anomalies and cholinergic neurodegeneration: role of APP-CTF.

Abstract

β-amyloid precursor protein (APP) and amyloid beta peptide (Aβ) are strongly implicated in Alzheimer's disease (AD) pathogenesis, although recent evidence has linked APP-βCTF generated by BACE1 (β-APP cleaving enzyme 1) to the development of endocytic abnormalities and cholinergic neurodegeneration in early AD. We show that partial BACE1 genetic reduction prevents these AD-related pathological features in the Ts2 mouse model of Down syndrome. Partially reducing BACE1 by deleting one BACE1 allele blocked development of age-related endosome enlargement in the medial septal nucleus, cerebral cortex, and hippocampus and loss of choline acetyltransferase (ChAT)-positive medial septal nucleus neurons. BACE1 reduction normalized APP-βCTF elevation but did not alter Aβ40 and Aβ42 peptide levels in brain, supporting a critical role in vivo for APP-βCTF in the development of these abnormalities. Although ameliorative effects of BACE1 inhibition on β-amyloidosis and synaptic proteins levels have been previously noted in AD mouse models, our results highlight the additional potential value of BACE1 modulation in therapeutic targeting of endocytic dysfunction and cholinergic neurodegeneration in Down syndrome and AD.

• Authors: Ying Jiang, Andrew Rigoglioso, Corrinne M Peterhoff, Monika Pawlik, Yutaka Sato, Cynthia Bleiwas, Philip Stavrides, John F Smiley, Stephen D Ginsberg, Paul M Mathews, Efrat Levy, Ralph A Nixon
• Journal: Neurobiology of aging (Neurobiol Aging) Vol. 39 Pg. 90-8 (Mar 2016) ISSN: 1558-1497 [Electronic] United States
• PMID: 26923405 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Choline O-Acetyltransferase
• Amyloid Precursor Protein Secretases
• Aspartic Acid Endopeptidases
• Bace1 protein, mouse

Topics

• Aging (genetics, pathology)
• Alleles
• Alzheimer Disease (genetics, pathology)
• Amyloid Precursor Protein Secretases (genetics, physiology)
• Amyloid beta-Peptides (physiology)
• Amyloid beta-Protein Precursor (physiology)
• Animals
• Aspartic Acid Endopeptidases (genetics, physiology)
• Choline O-Acetyltransferase (metabolism)
• Cholinergic Neurons (pathology)
• Disease Models, Animal
• Down Syndrome (genetics, pathology)
• Endosomes (genetics, pathology)
• Gene Deletion
• Genetic Association Studies
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Mice, Transgenic
• Nerve Degeneration (genetics, pathology)
• Septal Nuclei (cytology, enzymology)