Valproic acid inhibits Aβ production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models

Abstract

Neuritic plaques in the brains are one of the pathological hallmarks of Alzheimer ' s disease (AD). Amyloid ␤ -protein (A ␤ ), the central component of neuritic plaques, is derived from ␤ -amyloid precursor protein (APP) after ␤ -and ␥ -secretase cleavage. The molecular mechanism underlying the pathogenesis of AD is not yet well defi ned, and there has been no effective treatment for AD. Valproic acid (VPA) is one of the most widely used anticonvulsant and mood-stabilizing agents for treating epilepsy and bipolar disorder. We found that VPA decreased A ␤ production by inhibiting GSK-3 ␤ -mediated ␥ -secretase cleavage of APP both in vitro and in vivo. VPA treatment signifi cantly reduced neuritic plaque formation and improved memory defi cits in transgenic AD model mice. We also found that early application of VPA was important for alleviating memory defi cits of AD model mice. Our study suggests that VPA may be benefi cial in the prevention and treatment of AD.

An in vitro model for synaptic loss in neurodegenerative diseases suggests a neuroprotective role for valproic acid via inhibition of cPLA2 dependent signalling

“…VPA has been reported to reduce Aβ production (Qing et al, 2008b;Su et al, 2004) and attenuate neuronal loss in a murine transgenic model of Alzheimer's disease (Long et al, 2013). Our study showed that neither VPA nor PIA significantly altered the amounts of Aβ42 that bound to synapses.…”

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

“…Interestingly, although VPA downregulated APP protein levels, transcriptional inhibition of APP mRNA was not affected in pancreatic (BxPC3) and colon adenocarcinoma (SW480) cell lines as demonstrated previously (70).…”

Immunotherapeutic efficiency of a tetravalent Aβ1-15 vaccine in APP/PS1 transgenic mice as mouse model for Alzheimer’s disease

“…The mice trained to find the submerged platform in a 1.0-m-diameter pool of white, non-toxic colored water (temperature: 23°C). The procedure 34 consisted of 1 d of visible platform tests and 4 d of hidden platform tests, plus a probe trial 24 h after the last hidden platform test. In the visible platform test, mice were tested for 5 contiguous trials, with an intertrial interval of 30 min.…”