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

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 beta-peptide-42 (Abeta42) seems of major importance. Large extracellular deposits of aggregated Abeta42 (plaques) is a diagnostic feature of AD, but Abeta42 may be particularly cytotoxic when it accumulates inside neurons. The factors that may promote the intracellular accumulation of Abeta42 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 Abeta42 that is associated with cytotoxicity. The neurotoxicity of HA can be attenuated by an inhibitor of gamma-secretase, the enzyme activity that generates Abeta42, suggesting a key role for intracellular Abeta42 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 Abeta42 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.

Homocysteine Inhibits Hydrogen Peroxide Breakdown by Catalase

“…The association of homocysteine with disease states in which oxidative stress is a key component of the pathology is undisputed [22,23,[28][29][30]. Further there have been considerable studies in which homocysteine has been suggested to directly contribute to the oxidative stress [25,28,29,[34][35][36][37][38]. The suggestion that homocysteine can itself generate H 2 O 2 , with the assistance of Copper, has provided a proposed mechanism for this contribution [44][45][46].…”

“…In models of Alzheimer's disease homocysteine enhances the toxicity of the amyloid-ß peptide [34][35][36][37]. The strong links between homocysteine [38] and neurodegenerative disease suggests that these models would be useful to study if homocysteine has any action on catalase.…”

Open Label Clinical Trial of Hydrogen Brain Food for 91 Alzheimer's Patients (Targeting Therapy for Homocysteic Acid in Blood is an Alzheimer's Cognitive Recovery)

“…It has been reported that homocysteic acid (HA) is the probable pathogen of AD in blood [14][15][16][17], and it increases BBB permeability by NMDA receptor activation [18]. Especially it is interesting that HA can induce the amyloid β-42 which accumulated into neuronal cell [17].…”

“…Especially it is interesting that HA can induce the amyloid β-42 which accumulated into neuronal cell [17]. HA is known as a glutamate receptor agonist [19].…”

The Role of PP2A Methylation in Susceptibility and Resistance to TBI and AD-Induced Neurodegeneration

“…Elevated homocysteine levels in the blood or CSF of human subjects has been linked to an increased risk for AD (reviewed in : Zhuo et al, 2011(Zhuo et al, 2011, and this link between elevated levels of homocysteine and AD-like pathology or cognitive impairment has been reproduced in cell and animal models (Bernardo et al, 2007;Fuso et al, 2012b;Hasegawa et al, 2005;Kruman et al, 2002;Pacheco-Quinto et al, 2006;Rhodehouse et al, 2013;Sontag et al, 2007;Wei et al, 2011;Zhang et al, 2009;Zhuo et al, 2010;Zhuo and Pratico, 2010a, b). Several potential mechanisms have been proposed to explain the link between hyperhomocysteinemia and AD including oxidative stress, cerebrovascular damage, altered DNA methylation, Aβ elevation and tau protein phosphorylation (Fleming et al, 2012;Fuso et al, 2012a;Marlatt et al, 2008;Sontag et al, 2007;Sontag et al, 2008;Troen et al, 2008;Wei et al, 2011;Zhang et al, 2009;Zhuo et al, 2010).…”