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Preplaque ('preclinical') Aβ-induced inflammation and nerve growth factor deregulation in transgenic models of Alzheimer's disease-like amyloid pathology


Cuello, A C; Ferretti, M T; Iulita, M F (2012). Preplaque ('preclinical') Aβ-induced inflammation and nerve growth factor deregulation in transgenic models of Alzheimer's disease-like amyloid pathology. Neurodegenerative Diseases, 10(1-4):104-107.

Abstract

BACKGROUND: Alzheimer's disease (AD) neuropathology likely begins decades before clinical symptoms are manifested. Investigations on the early stages of the amyloid pathology are crucial for the discovery of diagnostic biomarkers or new therapeutic targets. Our transgenic (tg) animal models are most suitable to study early AD pathological events, as the pathology evolves in a well-staged manner, starting with intracellular Aβ accumulation and ending with plaque deposition.
OBJECTIVE: To determine the occurrence of key inflammatory markers and to look for signs of nerve growth factor (NGF) dysmetabolism at preplaque and postplaque stages in tg models of AD-like amyloid pathology and in human AD brains.
METHODS: We used our own tg lines (mice and rat), high-quality human brain material and applied neurochemical and immunohistochemical experimental approaches.
RESULTS: In both tg models, we observed an intracellular accumulation of oligomeric Aβ in cortical and hippocampal pyramidal neurons. This coincided with an upregulation of key inflammatory markers (iNOS, MHCII, COX-2) and a recruitment of microglia towards Aβ-burdened neurons. Using human AD brains, we showed alterations in the NGF metabolic pathway, which were mirrored in our tg rat model at early and late stages of amyloid plaque generation.
CONCLUSION: A proinflammatory process and, consequently, the deregulation of the NGF metabolic pathway could be amongst the earliest pathological events in the progression of AD.

Abstract

BACKGROUND: Alzheimer's disease (AD) neuropathology likely begins decades before clinical symptoms are manifested. Investigations on the early stages of the amyloid pathology are crucial for the discovery of diagnostic biomarkers or new therapeutic targets. Our transgenic (tg) animal models are most suitable to study early AD pathological events, as the pathology evolves in a well-staged manner, starting with intracellular Aβ accumulation and ending with plaque deposition.
OBJECTIVE: To determine the occurrence of key inflammatory markers and to look for signs of nerve growth factor (NGF) dysmetabolism at preplaque and postplaque stages in tg models of AD-like amyloid pathology and in human AD brains.
METHODS: We used our own tg lines (mice and rat), high-quality human brain material and applied neurochemical and immunohistochemical experimental approaches.
RESULTS: In both tg models, we observed an intracellular accumulation of oligomeric Aβ in cortical and hippocampal pyramidal neurons. This coincided with an upregulation of key inflammatory markers (iNOS, MHCII, COX-2) and a recruitment of microglia towards Aβ-burdened neurons. Using human AD brains, we showed alterations in the NGF metabolic pathway, which were mirrored in our tg rat model at early and late stages of amyloid plaque generation.
CONCLUSION: A proinflammatory process and, consequently, the deregulation of the NGF metabolic pathway could be amongst the earliest pathological events in the progression of AD.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute for Regenerative Medicine (IREM)
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2012
Deposited On:22 Jan 2013 12:48
Last Modified:16 Aug 2016 10:12
Publisher:Karger
ISSN:1660-2854
Publisher DOI:https://doi.org/10.1159/000333339
PubMed ID:22261363

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