Phenylbutyric acid reduces amyloid plaques and rescues cognitive behavior in AD transgenic mice

Abstract

SummaryTrafficking through the secretory pathway is known to regulate the maturation of the APP-cleaving secretases and APP proteolysis. The coupling of stress signaling and pathological deterioration of the brain in Alzheimer's disease (AD) supports a mechanistic connection between endoplasmic reticulum (ER) stress and neurodegeneration. Consequently, small molecular chaperones, which promote protein folding and minimize ER stress, might be effective in delaying or attenuating the deleterious progression of AD. We tested this hypothesis by treating APPswePS1delta9 AD transgenic mice with the molecular chaperone phenylbutyric acid (PBA) for 14 months at a dose of 1 mg PBA g)1 of body weight in the drinking water. Phenylbutyric acid treatment increased secretasemediated APP cleavage, but was not associated with any increase in amyloid biosynthesis. The PBA-treated AD transgenic mice had significantly decreased incidence and size of amyloid plaques throughout the cortex and hippocampus. There was no change in total amyloid levels suggesting that PBA modifies amyloid aggregation or pathogenesis independently of biogenesis. The decrease in amyloid plaques was paralleled by increased memory retention, as PBA treatment facilitated cognitive performance in a spatial memory task in both wild-type and AD transgenic mice. The molecular mechanism underlying the cognitive facilitation of PBA is not clear; however, increased levels of both metabotropic and ionotropic glutamate receptors, as well as ADAM10 and TACE, were observed in the cortex and hippocampus of PBA-treated mice. The data suggest that PBA ameliorates the cognitive and pathological features of AD and supports the investigation of PBA as a therapeutic for AD.

Histone deacetylase 6–mediated selective autophagy regulates COPD-associated cilia dysfunction

“…The chemical chaperone 4-phenyl butyric acid (4-PBA) has been previously shown to influence protein folding, protect against oxidative stress, and enhance the clearance of protein aggregates in vivo (57,58). Administration of 4-PBA for the duration of CS exposure also prevented CS-impaired MCC (P = 0.007) ( Figure 7D).…”

The Distinct Role of ADAM17 in APP Proteolysis and Microglial Activation Related to Alzheimer’s Disease

“…Treatment with acetylcholinesterase inhibitors (AChEIs), huprine X and huperzine A, can improve the cognitive performance in transgenic AD mouse model, also through ADAM17 activation (Ratia et al 2013). Molecular chaperone phenylbutyric acid (PBA) treatment for 14 months in transgenic AD mouse model can enhance ADAM17 activity, followed by modified amyloid aggregation, decreased amyloid plaques and increased memory retention (Wiley et al 2011).…”

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

“…Cognition enhancing drugs [Buccafusco, 2009;Husain and Mehta, 2011;Chen et al, 2014], bsecretase cleaving enzyme inhibitors [Sheridan, 2015], ApoE-directed therapeutics [Fonseca et al, 2009;Cramer et al, 2012;LaFerla, 2012;Strittmatter, 2012], HDACi [Peleg et al, 2010;Wiley et al, 2011;Govindarajan et al, 2012;Gr€ aff et al, 2012;Nebbioso et al, 2012;Ricobaraza et al, 2012;Sung et al, 2013;Coppedè, 2012;Falkenberg and Johnstone, 2014;Narayan et al, 2015], glycogen synthase kinase-3 inhibitors [Maqbool et al, 2016], polysulfides [Xu et al, 2014], retinoids [Fukasawa et al, 2012;Shearer et al, 2012], suppressing RAGE (receptor for advanced glycation end products) [Deane et al, 2012;Sorci et al, 2013], phosphodiesterase inhibitors [Feil et al, 2014;Gurney et al, 2015], and amyloid-targeting immunotherapies [Busche et al, 2015;Qian et al, 2015] are some of the more active areas of current AD drug development research.…”