Abstract
BackgroundAlzheimer’s Disease (AD) is a progressive neurodegenerative disease, especially affecting the hippocampus. Impairment of cognitive and memory functions is associated with amyloid β-peptide-induced oxidative stress and alterations in lipid metabolism. In this scenario, the dual role of peroxisomes in producing and removing ROS, and their function in fatty acids β-oxidation, may be critical. This work aims to investigating the possible involvement of peroxisomes in AD onset and progression, as studied in a transgenic mouse model, harboring the human Swedish familial AD mutation. We therefore characterized the peroxisomal population in the hippocampus, focusing on early, advanced, and late stages of the disease (3, 6, 9, 12, 18 months of age). Several peroxisome-related markers in transgenic and wild-type hippocampal formation were comparatively studied, by a combined molecular/immunohistochemical/ultrastructural approach.ResultsOur results demonstrate early and significant peroxisomal modifications in AD mice, compared to wild-type. Indeed, the peroxisomal membrane protein of 70 kDa and acyl-CoA oxidase 1 are induced at 3 months, possibly reflecting the need for efficient fatty acid β-oxidation, as a compensatory response to mitochondrial dysfunction. The concomitant presence of oxidative damage markers and the altered expression of antioxidant enzymes argue for early oxidative stress in AD. During physiological and pathological brain aging, important changes in the expression of peroxisome-related proteins, also correlating with ongoing gliosis, occur in the hippocampus. These age- and genotype-based alterations, strongly dependent on the specific marker considered, indicate metabolic and/or numerical remodeling of peroxisomal population.ConclusionsOverall, our data support functional and biogenetic relationships linking peroxisomes to mitochondria and suggest peroxisomal proteins as biomarkers/therapeutic targets in pre-symptomatic AD.
Highlights
Alzheimer’s Disease (AD) is a progressive neurodegenerative disease, especially affecting the hippocampus
We previously demonstrated that peroxisomes are involved in early stages of AD, as studied either in vivo, in a transgenic mouse model [18], or in vitro, on amyloid β-peptide (Aβ) treated cortical neurons [19]
The distribution of peroxisomes in Tg and WT hippocampal formation from 3, 6, 9, 12, and 18-month-old mice was investigated by analyzing the expression of peroxisomal membrane (PMP70, peroxin 14p (Pex14p)) and matrix (CAT, acyl-CoA oxidase 1 (AOX), THL) proteins
Summary
Alzheimer’s Disease (AD) is a progressive neurodegenerative disease, especially affecting the hippocampus. Impairment of cognitive and memory functions is associated with amyloid β-peptide-induced oxidative stress and alterations in lipid metabolism. In this scenario, the dual role of peroxisomes in producing and removing ROS, and their function in fatty acids β-oxidation, may be critical. Emergent studies have revealed that peroxisomes can function as intracellular signaling compartments and organizing platforms that orchestrate important developmental decisions from inside the cell [13]. These dynamic and versatile organelles respond to physiological and pathological changes in cellular environment by adapting their morphology, number and enzyme content [14]. We previously demonstrated that peroxisomes are involved in early stages of AD, as studied either in vivo, in a transgenic mouse model [18], or in vitro, on Aβ treated cortical neurons [19]
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