Homocysteic acid induces intraneuronal accumulation of neurotoxic Aβ42: Implications for the pathogenesis of Alzheimer's disease

摘要: The causes of neuronal dysfunction and degeneration in Alzheimer's disease (AD) are not fully understood, but increased production neurotoxic forms amyloid beta-peptide-42 (Abeta42) seems major importance. Large extracellular deposits aggregated Abeta42 (plaques) is a diagnostic feature AD, may be particularly cytotoxic when it accumulates inside neurons. factors that promote the intracellular accumulation AD unknown, recent findings suggest individuals with elevated homocysteine levels at risk for AD. We show homocysteic acid (HA), an oxidized metabolite homocysteine, induces intraneuronal associated cytotoxicity. neurotoxicity HA can attenuated by inhibitor gamma-secretase, enzyme activity generates Abeta42, suggesting key role action HA. Concentrations cerebrospinal fluid (CSF) were similar control subjects. CSF significantly patients, however, exacerbated HA-induced neurotoxicity, pathogenic These plays HA, potential therapeutic benefit agents modify actions homocysteine.