Homocysteine exacerbates β‐amyloid pathology, tau pathology, and cognitive deficit in a mouse model of Alzheimer disease with plaques and tangles

Abstract

Objective High level of homocysteine (Hcy) is a recognized risk factor for developing Alzheimer disease (AD). However, the mechanisms involved are unknown. Previously, it was shown that high Hcy increases brain b-amyloid (Ab) levels in amyloid precursor protein transgenic mice, but no data are available on the effect that it may have on the other main pathologic features of AD such as tau. Methods 3xTg mice with diet-induced high Hcy were compared with mice having normal Hcy. Neuronal cells were incubated with and without Hcy. Results Diet-induced high Hcy resulted in an exacerbation of the entire AD-like phenotype of the 3xTg mice. In particular, we found that compared with controls, mice with high Hcy developed significant memory and learning deficits, and had elevated Ab levels and deposition, which was mediated by an activation of the γ-secretase pathway. In addition, the same mice had a significant increase in the insoluble fraction of tau and its phosphorylation at specific epitopes, which was mediated by the cdk5 pathway. In vitro studies confirmed these observations and provided evidence that the effects of Hcy on Ab and tau are independent from each other. Interpretation Taken together, our findings demonstrate that a dietary condition that leads to an elevation of Hcy levels results in an exacerbation of all 3 major pathological features of the AD phenotype: memory deficits, and Ab and tau neuropathology. They support the concept that this dietary lifestyle can act as a risk factor and actively contribute to the development of the disease.

The involvement of homocysteine in stress-induced Aβ precursor protein misprocessing and related cognitive decline in rats

“…The results from the Hcy-targeting intervention experiment strongly suggested that the stressinduced HHcy and subsequent up-regulation of Aβ could be one of the mechanisms of stress affecting the development of cognitive decline. A similar role for Hcy in Aβ pathogenesis has also been proved in transgenic AD mice with diet-induced HHcy (Li et al 2014) and in normal rats receiving daily Hcy injections (Chai et al 2013;Zhang et al 2009). These studies reported that Hcy could disturb the metabolism of Aβ and induce Aβ accumulation and cognition impairment both in AD or normal rodents.…”

“…Aβ1-40 and Aβ1-42 levels in hippocampal and cerebral extracts were assayed by sensitive sandwich ELISA kits (Wako Chemicals, Richmond, VA) according to the protocol described by the manufacturer (Li et al 2014).…”

Brain 5‐lipoxygenase over‐expression worsens memory, synaptic integrity, and tau pathology in the P301S mice

“…Testing was always performed in the same room and at the same time to ensure environmental consistency as previously described (Di Meco et al ., 2014; Li et al ., 2014). Briefly, each mouse was placed in the center of the Y‐maze and allowed to explore freely during a 5‐min session as a measure of spontaneous alternating behavior.…”

“…To perform the Morris water maze (MWM), we used a white circular plastic tank (122 cm in diameter, walls 76 cm high), filled with water maintained at 22°±2°C, and made opaque by the addition of a nontoxic white paint, as previously described (Di Meco et al ., 2014; Li et al ., 2014). Mice were trained for four consecutive days to find a Plexiglas platform submerged in water from four different starting points.…”

“…The assay for insoluble tau was performed as previously described (Li et al ., 2014). Briefly, ultracentrifugation and sarkosyl extraction (30 min in 1% sarkosyl) was used to obtain soluble and insoluble fractions of tau from brain homogenates.…”