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

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Abstract
The causes of neuronal dysfunction and degeneration in Alzheimer's disease (AD) are not fully understood, but increased production of neurotoxic forms of amyloid β‐peptide‐42 (Aβ42) seems of major importance. Large extracellular deposits of aggregated Aβ42 (plaques) is a diagnostic feature of AD, but Aβ42 may be particularly cytotoxic when it accumulates inside neurons. The factors that may promote the intracellular accumulation of Aβ42 in AD are unknown, but recent findings suggest that individuals with elevated homocysteine levels are at increased risk for AD. We show that homocysteic acid (HA), an oxidized metabolite of homocysteine, induces intraneuronal accumulation of a Aβ42 that is associated with cytotoxicity. The neurotoxicity of HA can be attenuated by an inhibitor of γ‐secretase, the enzyme activity that generates Aβ42, suggesting a key role for intracellular Aβ42 accumulation in the neurotoxic action of HA. Concentrations of HA in cerebrospinal fluid (CSF) were similar in AD and control subjects. CSF homocysteine levels were elevated significantly in AD patients, however, and homocysteine exacerbated HA‐induced neurotoxicity, suggesting a role for HA in the pathogenic action of elevated homocysteine levels in AD. These findings suggest that the intracellular accumulation of Aβ42 plays a role in the neurotoxic action of HA, and suggest a potential therapeutic benefit of agents that modify the production and neurotoxic actions of HA and homocysteine.