APP Overexpression Causes Aβ-Independent Neuronal Death through Intrinsic Apoptosis Pathway
| Autor: | Li Bai, Ning Cheng, Ankita Gumaste, Song Jiao, Leonardo Belluscio |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Olfactory system
Genetically modified mouse Blotting Western Enzyme-Linked Immunosorbent Assay Mice Transgenic amyloid precursor protein Biology 03 medical and health sciences Amyloid beta-Protein Precursor 0302 clinical medicine Alzheimer Disease medicine Amyloid precursor protein Animals Aspartic Acid Endopeptidases Humans 030304 developmental biology Membrane Potential Mitochondrial Neurons 0303 health sciences General Neuroscience Intrinsic apoptosis Neurodegeneration apoptosis neurodegeneration Brain General Medicine New Research medicine.disease olfactory Immunohistochemistry Caspase 9 Disease Models Animal Microscopy Electron Apoptosis biology.protein Disorders of the Nervous System Alzheimer's disease Amyloid Precursor Protein Secretases Neuroscience Amyloid precursor protein secretase 030217 neurology & neurosurgery |
| Zdroj: | eNeuro |
| ISSN: | 2373-2822 |
| Popis: | Accumulation of amyloid-β (Aβ) peptide in the brain is a central hallmark of Alzheimer’s disease (AD) and thought to be the cause of the observed neurodegeneration. Many animal models have been generated that over-produce 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, 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 caspase9 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. Significance Statement: Understanding the basis of neural loss in Alzheimer’s disease (AD) is fundamental to understanding disease progression and developing new diagnostic and treatment strategies. Olfactory loss occurs early in AD and offers a unique perspective into the neurodegenerative process. Here we show that overexpression of hAPP can cause early apoptosis of olfactory sensory neurons in the absence of Aβ peptide and in a cell-autonomous manner. We further demonstrate activation of the intrinsic apoptosis pathway in hAPP expressing neurons highlighting a potential role for cellular stress and mitochondrial regulatory factors in mediating this early neural loss. |
| Databáze: | OpenAIRE |
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