Amylin Treatment Reduces Neuroinflammation and Ameliorates Abnormal Patterns of Gene Expression in the Cerebral Cortex of an Alzheimer’s Disease Mouse Model

Abstract

Our recent study has demonstrated that peripheral amylin treatment reduces the amyloid pathology in the brain of Alzheimer’s disease (AD) mouse models, and improves their learning and memory. We hypothesized that the beneficial effects of amylin for AD was beyond reducing the amyloids in the brain, and have now directly tested the actions of amylin on other aspects of AD pathogenesis, especially neuroinflammation. A 10-week course of peripheral amylin treatment significantly reduced levels of cerebral inflammation markers, Cd68 and Iba1, in amyloid precursor protein (APP) transgenic mice. Mechanistic studies indicated the protective effect of amylin required interaction with its cognate receptor because silencing the amylin receptor expression blocked the amylin effect on Cd68 in microglia. Using weighted gene co-expression network analysis, we discovered that amylin treatment influenced two gene modules linked with amyloid pathology: 1) a module related to proinflammation and transport/vesicle process that included a hub gene of Cd68, and 2) a module related to mitochondria function that included a hub gene of Atp5b. Amylin treatment restored the expression of most genes in the APP cortex toward levels observed in the wild-type (WT) cortex in these two modules including Cd68 and Atp5b. Using a human dataset, we found that the expression levels of Cd68 and Atp5b were significantly correlated with the neurofibrillary tangle burden in the AD brain and with their cognition. These data suggest that amylin acts on the pathological cascade in animal models of AD, and further supports the therapeutic potential of amylin-type peptides for AD.

Amylin Enhances Amyloid-β Peptide Brain to Blood Efflux Across the Blood-Brain Barrier

“…We and others have reported Ramp1 and Ramp3 are expressed in the mouse brain [38, 39]. Here, to confirm their expression in bEnd3 we first performed pilot studies to identify the amylin receptor expressed in these cells.…”

Amylin and its G-protein-coupled receptor: A probable pathological process and drug target for Alzheimer’s disease

“…Using a microglial cell line, BV-2, we found that CD68 expression stimulated by LPS was downregulated by adding low concentrations of amylin. In contrast, CD68 expression was not influenced by the media addition of a high concentration of amylin (Wang et al, 2017). In the activated microglia cells, we validated that the amylin-induced attenuation of CD68 expression is mediated by binding to AmR by knocking-down the amylin receptor.…”

“…Two well-documented markers for activated microglia, i.e., ionized calcium-binding adaptor (Iba-1) (Paquet et al, 2014; Zotova et al, 2013) and CD68 (Arnold et al, 2000), were examined in the brains of AD mouse models by immunostaining for the effects of amylin treatment on neuroinflammation in the AD brain. While amylin treatment significantly reduced the number of Iba-1+ microglia cells at the cortex, thalamus and hippocampus, amylin treatment modestly but significantly reduced the number of CD68+ microglia at the cortex region in AD mouse models (Wang et al, 2017; Zhu et al, 2017b). The expression levels of inflammatory cytokines IFNγ and IL-1β were also reduced by amylin treatment.…”

“…However, no effective drug has yet been developed to target neuroinflammation in the brain. Our research examined whether peripheral treatment with amylin influenced neuroinflammation in the AD brain (Wang et al, 2017; Zhu et al, 2017b). Two well-documented markers for activated microglia, i.e., ionized calcium-binding adaptor (Iba-1) (Paquet et al, 2014; Zotova et al, 2013) and CD68 (Arnold et al, 2000), were examined in the brains of AD mouse models by immunostaining for the effects of amylin treatment on neuroinflammation in the AD brain.…”

“…Specifically, amylin treatment influenced two modules of gene expressions 1) related to neuroinflammation that included a hub gene of CD68 and 2) related to mitochondrial function that included a hub gene of ATP5B (Wang et al, 2017). Using human data, we found that orthologues of these hub genes, including CD68 and ATP5B, strongly correlated with neurofibrillary tangles in the AD brain and with Mini-Mental Status Examination scores.…”