Abstract
Extracellular matrix (ECM) molecules and growth factors, such as fibroblast growth factor (FGF), play a crucial role in Alzheimer's disease (AD). The purpose of this investigation was to determine whether phenotypic alterations in ECM production are present in non-neuronal AD cells associated with different FGF expression and response. Synthesis of glycosaminoglycans (GAG) and collagen were measured in skin fibroblasts from patients with familial, sporadic AD (FAD and SAD respectively), and from age-matched controls by radiolabeled precursors. Proteoglycans (PG), metalloprotease (MMP)-1, and FGF gene expressions were measured by reverse transcription-polymerase chain reaction. The results showed different ECM neosynthesis and mRNA levels in the two AD fibroblast populations. FAD accumulated more collagen and secreted less GAG than SAD. Biglycan PG was upregulated in FAD while betaglycan, syndecan, and decorin were markedly downregulated in SAD fibroblasts. We found a significant decrease of MMP1, more marked in FAD than in SAD fibroblasts. Constitutive FGF expression was greatly reduced in both pathological conditions (SAD>FAD). Moreover, an inverse high affinity/low affinity FGF receptor ratio between SAD and FAD fibroblasts was observed. FGF treatment differently modulated ECM molecule production and gene expression in the two cell populations. These observations in association with the changes in FGF gene expression and in the FGF receptor number, suggest that cellular mechanisms downstream from FGF receptor binding are involved in the two different forms of AD.
Highlights
Alzheimer’s disease (AD) accounts for about 50 to 70 percent of dementia disorders
Cell Cultures Primary human fibroblast cultures were obtained from skin biopsies of AD patients and from normal subjects at the Department of Neurology, University of Florence after informed consent was given from all subjects or, where appropriate, from their caregivers
fibroblast growth factor (FGF) treatment significantly enhanced cell number only in control and sporadic type (SAD) fibroblasts
Summary
Alzheimer’s disease (AD) accounts for about 50 to 70 percent of dementia disorders. It is pathologically characterized by intracellular neurofibrillary tangles as the result of hyperphosphorylated microtubule-associated protein tau accumulation, as well as extracellular amyloid deposits, called senile plaques [1], with a progressive accumulation of insoluble amyloid in brain parenchyma and vasculature. Senile plaques are mainly composed of βamyloid (Aβ) peptide which is generated by the anomalous endoproteolytic processing of the amyloid precursor protein (APP). About ten percent of AD cases appear to be related to mutations in the APP gene or in the presenilin genes, PS1 or PS2 [2]. The majority of adult onset AD cases are not genetically transmitted and are considered multifactorial sporadic type (SAD)
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