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Behavioral and neural network abnormalities in human APP transgenic mice resemble those of App knock-in mice and are modulated by familial Alzheimer’s disease mutations but not by inhibition of BACE1

التفاصيل البيبلوغرافية
العنوان: Behavioral and neural network abnormalities in human APP transgenic mice resemble those of App knock-in mice and are modulated by familial Alzheimer’s disease mutations but not by inhibition of BACE1
المؤلفون: Jorge J. Palop, Biljana Djukic, Pascal E. Sanchez, Jeanne T. Paz, Kaitlyn Ho, Xinxing Yu, Lennart Mucke, Michael Gill, Weiping Zhang, Isabel Lopez, Erik C. B. Johnson, Gui-Qiu Yu, Melanie Das
المصدر: Molecular Neurodegeneration
Molecular neurodegeneration, vol 15, iss 1
Molecular Neurodegeneration, Vol 15, Iss 1, Pp 1-26 (2020)
بيانات النشر: BioMed Central, 2020.
سنة النشر: 2020
مصطلحات موضوعية: 0301 basic medicine, Aging, App NL-G-F, Knock-in, Neurodegenerative, lcsh:Geriatrics, Hippocampal formation, Inbred C57BL, Transgenic, lcsh:RC346-429, Pathogenesis, I5, Mice, Amyloid beta-Protein Precursor, 0302 clinical medicine, Amyloid precursor protein, Aspartic Acid Endopeptidases, 2.1 Biological and endogenous factors, Gene Knock-In Techniques, Aetiology, Behavior, Animal, biology, Brain, Alzheimer's disease, Cell biology, Neurological, Alzheimer’s disease, APP-KI, Research Article, Genetically modified mouse, Amyloid, Inhibitor, C-Fos, Transgene, Clinical Sciences, Mice, Transgenic, Learning and memory, 03 medical and health sciences, Cellular and Molecular Neuroscience, SWD, Alzheimer Disease, Gene knockin, mental disorders, Acquired Cognitive Impairment, Genetics, Animals, Humans, BACE, Molecular Biology, lcsh:Neurology. Diseases of the nervous system, Epileptiform, Behavior, Neurology & Neurosurgery, Calbindin, Epilepsy, Animal, AppNL-G-F, Wild type, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Molecular medicine, Brain Disorders, Mice, Inbred C57BL, Disease Models, Animal, lcsh:RC952-954.6, 030104 developmental biology, App(NL-G-F), Oligomers, Disease Models, Mutation, biology.protein, Dementia, Neurology (clinical), Nerve Net, Amyloid Precursor Protein Secretases, J20, APP, 030217 neurology & neurosurgery
الوصف: Background Alzheimer’s disease (AD) is the most frequent and costly neurodegenerative disorder. Although diverse lines of evidence suggest that the amyloid precursor protein (APP) is involved in its causation, the precise mechanisms remain unknown and no treatments are available to prevent or halt the disease. A favorite hypothesis has been that APP contributes to AD pathogenesis through the cerebral accumulation of the amyloid-β peptide (Aβ), which is derived from APP through sequential proteolytic cleavage by BACE1 and γ-secretase. However, inhibitors of these enzymes have failed in clinical trials despite clear evidence for target engagement. Methods To further elucidate the roles of APP and its metabolites in AD pathogenesis, we analyzed transgenic mice overexpressing wildtype human APP (hAPP) or hAPP carrying mutations that cause autosomal dominant familial AD (FAD), as well as App knock-in mice that do not overexpress hAPP but have two mouse App alleles with FAD mutations and a humanized Aβ sequence. Results Although these lines of mice had marked differences in cortical and hippocampal levels of APP, APP C-terminal fragments, soluble Aβ, Aβ oligomers and age-dependent amyloid deposition, they all developed cognitive deficits as well as non-convulsive epileptiform activity, a type of network dysfunction that also occurs in a substantive proportion of humans with AD. Pharmacological inhibition of BACE1 effectively reduced levels of amyloidogenic APP C-terminal fragments (C99), soluble Aβ, Aβ oligomers, and amyloid deposits in transgenic mice expressing FAD-mutant hAPP, but did not improve their network dysfunction and behavioral abnormalities, even when initiated at early stages before amyloid deposits were detectable. Conclusions hAPP transgenic and App knock-in mice develop similar pathophysiological alterations. APP and its metabolites contribute to AD-related functional alterations through complex combinatorial mechanisms that may be difficult to block with BACE inhibitors and, possibly, also with other anti-Aβ treatments.
وصف الملف: application/pdf
اللغة: English
تدمد: 1750-1326
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0789322d9d12b4d8e8bef6dc52aae963
http://europepmc.org/articles/PMC7489007
حقوق: OPEN
رقم الأكسشن: edsair.doi.dedup.....0789322d9d12b4d8e8bef6dc52aae963
قاعدة البيانات: OpenAIRE
الوصف
تدمد:17501326