Does Intraneuronal Accumulation of Carboxyl-terminal Fragments of the Amyloid Precursor Protein Trigger Early Neurotoxicity in Alzheimer’s Disease?
Autor: | Inger Lauritzen, Raphaëlle Pardossi-Piquard, Frédéric Checler, Anaïs Bécot, Alexandre Bourgeois |
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Přispěvatelé: | Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA) |
Rok vydání: | 2019 |
Předmět: |
Genetically modified mouse
[SDV]Life Sciences [q-bio] C-terminal APP fragments memory-related behavior Amyloid beta-Protein Precursor 03 medical and health sciences 0302 clinical medicine Alzheimer Disease Extracellular Amyloid precursor protein medicine Animals Humans Senile plaques C99 Neuroinflammation 030304 developmental biology 0303 health sciences dimerization biology synaptic dysfunction Chemistry Autophagy Neurotoxicity Alzheimer's disease medicine.disease animal models Peptide Fragments Cell biology C83 endolysosomalautophagic dysfunction Neurology biology.protein [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Neurology (clinical) Antibody brain network alterations 030217 neurology & neurosurgery |
Zdroj: | Current Alzheimer Research Current Alzheimer Research, Bentham Science Publishers, 2019, 16 (5), pp.453-457. ⟨10.2174/1567205016666190325092841⟩ |
ISSN: | 1567-2050 |
Popis: | Background: Alzheimer’s disease (AD) is associated with extracellular accumulation and aggregation of amyloid β (Aβ) peptides ultimately seeding in senile plaques. Recent data show that their direct precursor C99 (βCTF) also accumulates in AD-affected brain as well as in AD-like mouse models. C99 is consistently detected much earlier than Aβ, suggesting that this metabolite could be an early contributor to AD pathology. C99 accumulates principally within endolysosomal and autophagic structures and its accumulation was described as both a consequence and one of the causes of endolysosomalautophagic pathology, the occurrence of which has been documented as an early defect in AD. C99 was also accompanied by C99-derived C83 (αCTF) accumulation occurring within the same intracellular organelles. Both these CTFs were found to dimerize leading to the generation of higher molecular weight CTFs, which were immunohistochemically characterized in situ by means of aggregate-specific antibodies. Discussion: Here, we discuss studies demonstrating a direct link between the accumulation of C99 and C99-derived APP-CTFs and early neurotoxicity. We discuss the role of C99 in endosomal-lysosomalautophagic dysfunction, neuroinflammation, early brain network alterations and synaptic dysfunction as well as in memory-related behavioral alterations, in triple transgenic mice as well as in newly developed AD animal models. Conclusion: This review summarizes current evidence suggesting a potential role of the β -secretasederived APP C-terminal fragment C99 in Alzheimer’s disease etiology |
Databáze: | OpenAIRE |
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