title: 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.affiliation: Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY, USA; Department of Psychiatry, NYU Langone Medical Center, New York, NY, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Rigoglioso
authors.affiliation: Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY, USA.
authors.forename: Corrinne M
authors.initials: CM
authors.lastname: Peterhoff
authors.affiliation: Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY, USA.
authors.forename: Monika
authors.initials: M
authors.lastname: Pawlik
authors.affiliation: Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY, USA.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Bleiwas
authors.affiliation: Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Stavrides
authors.affiliation: Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY, USA; Department of Psychiatry, NYU Langone Medical Center, New York, NY, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Smiley
authors.affiliation: Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY, USA; Department of Psychiatry, NYU Langone Medical Center, New York, NY, USA; Department of Neuroscience & Physiology, NYU Langone Medical Center, New York, NY, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Ginsberg
authors.affiliation: Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY, USA; Department of Psychiatry, NYU Langone Medical Center, New York, NY, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Mathews
authors.affiliation: Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY, USA; Department of Psychiatry, NYU Langone Medical Center, New York, NY, USA; Department of Biochemistry and Molecular Pharmacology, NYU Langone Medical Center, New York, NY, USA.
authors.forename: Efrat
authors.initials: E
authors.lastname: Levy
authors.affiliation: Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY, USA; Department of Psychiatry, NYU Langone Medical Center, New York, NY, USA; Department of Cell Biology, NYU Langone Medical Center, New York, NY, USA. Electronic address: nixon@nki.rfmh.org.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Nixon
mesh_terms: D000375:Aging / Q000235:genetics / Q000473:pathology; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000502:physiology*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000502:physiology*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D059329:Cholinergic Neurons / Q000473:pathology*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics* / Q000473:pathology*; D011992:Endosomes / Q000235:genetics / Q000473:pathology*; D017353:Gene Deletion; D056726:Genetic Association Studies; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology*; D012686:Septal Nuclei / Q000166:cytology / Q000201:enzymology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002795:Choline O-Acetyltransferase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: APP-βCTF; Alzheimer's disease; BACE1; Basal forebrain cholinergic neurons; Endosomes; Trisomic mice