title: APP Overexpression Causes Aβ-Independent Neuronal Death through Intrinsic Apoptosis Pathway.
abstract: Accumulation of amyloid-β (Aβ) peptide in the brain is a central hallmark of Alzheimer's disease (AD) and is thought to be the cause of the observed neurodegeneration. Many animal models have been generated that overproduce Aβ yet do not exhibit clear neuronal loss, questioning this Aβ hypothesis. We previously developed an in vivo mouse model that expresses a humanized amyloid precursor protein (hAPP) in olfactory sensory neurons (OSNs) showing robust apoptosis and olfactory dysfunction by 3 weeks of age, which is consistent with early OSN loss and smell deficits, as observed in AD patients. Here we show, by deleting the β-site APP cleaving enzyme 1 (BACE1) in two distinct transgenic mouse models, that hAPP-induced apoptosis of OSNs is Aβ independent and remains cell autonomous. In addition, we reveal that the intrinsic apoptosis pathway is responsible for hAPP-induced OSN death, as marked by mitochondrial damage and caspase-9 activation. Given that hAPP expression causes OSN apoptosis despite the absence of BACE1, we propose that Aβ is not the sole cause of hAPP-induced neurodegeneration and that the early loss of olfactory function in AD may be based on a cell-autonomous mechanism, which could mark an early phase of AD, prior to Aβ accumulation. Thus, the olfactory system could serve as an important new platform to study the development of AD, providing unique insight for both early diagnosis and intervention.
authors: Developmental Neural Plasticity Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, Maryland 20892.
authors: Ning
authors: N
authors: Cheng
authors: Developmental Neural Plasticity Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, Maryland 20892.
authors: Song
authors: S
authors: Jiao
authors: Developmental Neural Plasticity Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, Maryland 20892.
authors: Ankita
authors: A
authors: Gumaste
authors: Developmental Neural Plasticity Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, Maryland 20892.
authors: Li
authors: L
authors: Bai
authors: Developmental Neural Plasticity Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, Maryland 20892.
authors: Leonardo
authors: L
authors: Belluscio
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D053453:Caspase 9 / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009474:Neurons / Q000378:metabolism* / Q000473:pathology
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; C506434:Casp9 protein, mouse; D053453:Caspase 9; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: amyloid precursor protein; apoptosis; neurodegeneration; olfactory