Acetyl-L-carnitine-induced up-regulation of heat shock proteins protects cortical neurons against amyloid-beta peptide 1–42-mediated oxidative stress and neurotoxicity: Implications for Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by loss of memory and cognition and by senile plaques and neurofibrillary tangles in brain. Amyloid-beta peptide, particularly the 42-amino-acid peptide (Abeta(1-42)), is a principal component of senile plaques and is thought to be central to the pathogenesis of the disease. The AD brain is under significant oxidative stress, and Abeta(1-42) peptide is known to cause oxidative stress in vitro and in vivo. Acetyl-L-carnitine (ALCAR) is an endogenous mitochondrial membrane compound that helps to maintain mitochondrial bioenergetics and lowers the increased oxidative stress associated with aging. Glutathione (GSH) is an important endogenous antioxidant, and its levels have been shown to decrease with aging. Administration of ALCAR increases cellular levels of GSH in rat astrocytes. In the current study, we investigated whether ALCAR plays a protective role in cortical neuronal cells against Abeta(1-42)-mediated oxidative stress and neurotoxicity. Decreased cell survival in neuronal cultures treated with Abeta(1-42) correlated with an increase in protein oxidation (protein carbonyl, 3-nitrotyrosine) and lipid peroxidation (4-hydroxy-2-nonenal) formation. Pretreatment of primary cortical neuronal cultures with ALCAR significantly attenuated Abeta(1-42)-induced cytotoxicity, protein oxidation, lipid peroxidation, and apoptosis in a dose-dependent manner. Addition of ALCAR to neurons also led to an elevated cellular GSH and heat shock proteins (HSPs) levels compared with untreated control cells. Our results suggest that ALCAR exerts protective effects against Abeta(1-42) toxicity and oxidative stress in part by up-regulating the levels of GSH and HSPs. This evidence supports the pharmacological potential of acetyl carnitine in the management of Abeta(1-42)-induced oxidative stress and neurotoxicity. Therefore, ALCAR may be useful as a possible therapeutic strategy for patients with AD.

Involvement of PI3K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-L-carnitine and α-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: Implications for Alzheimer's disease

“…We previously have shown that ALCAR protected neurons against Aβ (1-42)-induced oxidative stress, mitochondrial dysfunction and neurotoxicity, in primary cortical cultures (51). In the present study, we show that ALCAR+LA pretreatment, protected against HNEinduced oxidative stress (protein oxidation and lipid-peroxidation), mitochondrial dysfunction and neurotoxicity in cortical cultures.…”

Collaboration of geldanamycin-activated P70S6K and Hsp70 against beta-amyloid-induced hippocampal apoptosis: an approach to long-term memory and learning

“…Evidence for activation of the oxidative stress pathway starts from CA3 sector in the hippocampus and leads to a progressive hippocampal apoptosis and atrophy (Cruz-Sánchez et al 2010). The dual effect of Hsps in execution of Aβ-induced, oxidative stress-mediated apoptosis has been demonstrated (Abdul et al 2006). Here, we observed that Aβ-depleted GSH, an indicator of oxidative stress, caused a mild increase in Hsp90 and Hsp70 levels.…”

Quantitative proteomic analysis of differentially expressed proteins in Aβ(17-42) treated synaptosomes

“…One such cellular stress response is heat shock proteins, which protect cells from various forms of stress. Heat shock proteins serve as molecular chaperones which exist in various types including Hsp32 (also known as heme oxygenase-1), Hsp60, and Hsp72 all of which have been shown to play a protective role in the brain in regard to oxidative stress 31 . Heat shock cognate (Hsc71), an isoform of Hsp73, is employed by the cell as a primary defense against unfavorable conditions.…”