Dataset Information

Amylin receptor ligands reduce the pathological cascade of Alzheimer's disease.

ABSTRACT: Amylin is an important gut-brain axis hormone. Since amylin and amyloid-? peptide (A?) share similar ? sheet secondary structure despite not having the same primary sequences, we hypothesized that the accumulation of A? in the brains of subjects with Alzheimer's disease (AD) might compete with amylin for binding to the amylin receptor (AmR). If true, adding exogenous amylin type peptides would compete with A? and reduce the AD pathological cascade, improving cognition. Here we report that a 10-week course of peripheral treatment with human amylin significantly reduced multiple different markers associated with AD pathology, including reducing levels of phospho-tau, insoluble tau, two inflammatory markers (Iba1 and CD68), as well as cerebral A?. Amylin treatment also led to improvements in learning and memory in two AD mouse models. Mechanistic studies showed that an amylin receptor antagonist successfully antagonized some protective effects of amylin in vivo, suggesting that the protective effects of amylin require interaction with its cognate receptor. Comparison of signaling cascades emanating from AmR suggest that amylin electively suppresses activation of the CDK5 pathway by A?. Treatment with amylin significantly reduced CDK5 signaling in a receptor dependent manner, dramatically decreasing the levels of p25, the active form of CDK5 with a corresponding reduction in tau phosphorylation. This is the first report documenting the ability of amylin treatment to reduce tauopathy and inflammation in animal models of AD. The data suggest that the clinical analog of amylin, pramlintide, might exhibit utility as a therapeutic agent for AD and other neurodegenerative diseases.

SUBMITTER: Zhu H

PROVIDER: S-EPMC6511375 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Amylin receptor ligands reduce the pathological cascade of Alzheimer's disease.

Zhu Haihao H Xue Xiehua X Wang Erming E Wallack Max M Na Hana H Hooker Jacob M JM Kowall Neil N Tao Qiushan Q Stein Thor D TD Wolozin Benjamin B Qiu Wei Qiao WQ

Neuropharmacology 20170328

Amylin is an important gut-brain axis hormone. Since amylin and amyloid-β peptide (Aβ) share similar β sheet secondary structure despite not having the same primary sequences, we hypothesized that the accumulation of Aβ in the brains of subjects with Alzheimer's disease (AD) might compete with amylin for binding to the amylin receptor (AmR). If true, adding exogenous amylin type peptides would compete with Aβ and reduce the AD pathological cascade, improving cognition. Here we report that a 10-w ...[more]

PMID: 28363773

Similar Datasets

Project description:BACKGROUND:Alzheimer's disease (AD) is characterized by physiologically endogenous proteins amyloid beta (A?) and tau undergoing a conformational change and accumulating as soluble oligomers and insoluble aggregates. Tau and A? soluble oligomers, which contain extensive ?-sheet secondary structure, are thought to be the most toxic forms. The objective of this study was to determine the ability of TWF9, an anti-?-sheet conformation antibody (a?ComAb), to selectively recognize pathological A? and phosphorylated tau in AD human tissue compared with cognitively normal age-matched controls and to improve the performance of old 3xTg-AD mice with advanced pathology in behavioral testing after acute treatment with TWF9. METHODS:In this study, we used immunohistochemistry, immunoprecipitation, and enzyme-linked immunosorbent assay (ELISA) to characterize TWF9 specificity. We further assessed cognitive performance in old (18-22 months) 3xTg-AD mice using both a Barnes maze and novel object recognition after intraperitoneal administration of TWF9 (4 mg/kg) biweekly for 2 weeks before the start of behavioral testing. Injections continued for the duration of the behavioral testing, which lasted 2 weeks. RESULTS:Histological analysis of TWF9 in formalin-fixed paraffin-embedded human control and AD (ABC score: A3B3C3) brain tissue revealed preferential cytoplasmic immunoreactivity in neurons in the AD tissue compared with controls (p?<?0.05). Furthermore, ELISA using oligomeric and monomeric A? showed a preferential affinity for oligomeric A?. Immunoprecipitation studies showed that TWF9 extracted both phosphorylated tau (p?<?0.01) and A? (p?<?0.01) from fresh frozen brain tissues. Results show that treated old 3xTg-AD mice have an enhanced novel object recognition memory (p?<?0.01) and Barnes maze performance (p?=?0.05) compared with control animals. Overall plaque burden, neurofibrillary tangles, microgliosis, and astrocytosis remained unchanged. Soluble phosphorylated tau was significantly reduced in TWF9-treated mice (p?<?0.05), and there was a trend for a reduction in soluble A? levels in the brain homogenates of female 3xTg-AD mice (p?=?0.06). CONCLUSIONS:This study shows that acute treatment with an a?ComAb can effectively improve performance in behavioral testing without reduction of amyloid plaque burden, and that peripherally administered IgG can affect levels of pathological species in the brain.

Project description:Alzheimer's disease is a rather complex neurodegenerative disease, which is attributed to a combination of multiple factors. Among the many pathological pathways, synaptic dysfunctions, such as synapses loss and deficits in synaptic plasticity, were thought to be strongly associated with cognitive decline. The deficiencies in various sorts of neurotransmissions are responsible for the multifarious neurodegenerative symptoms in Alzheimer's disease, for example, the cholinergic and glutamatergic deficits for cognitive decline, the excitatory and inhibitory neurotransmission dyshomeostasis for synaptic plasticity deficits and epileptiform symptoms, and the monoamine neurotransmission for neuropsychiatric symptoms. Amyloid cascade hypothesis is the most popular pathological theory to explain Alzheimer's disease pathogenesis and attracts considerable attention. Multiple lines of genetic and pathological evidence support the predominant role of amyloid beta in Alzheimer's disease pathology. Neurofibrillary tangles assembled by microtubule-associated protein tau are other important histopathological characteristics in Alzheimer's disease brains. Cascade of tau toxicity was proved to lead to neuron damage, neuroinflammation and oxidative stress in brain. Ageing is the main risk factor of neurodegenerative diseases, and is associated with inflammation, oxidative stress, reduced metabolism, endocrine insufficiencies and organ failures. These aging related risk factors were also proved to be some of the risk factors contributing to Alzheimer's disease. In Alzheimer's disease drug development, many good therapeutic strategies have been investigated in clinical evaluations. However, complex mechanism of Alzheimer's disease and the interplay among different pathological factors call for the come out of all-powerful therapies with multiple curing functions. This review seeks to summarize some of the representative treatments targeting different pathological pathways currently under clinical evaluations. Multi-target therapies as an emerging strategy for Alzheimer's disease treatment will be highlighted.

Dataset Information

Amylin receptor ligands reduce the pathological cascade of Alzheimer's disease.

Publications

Amylin receptor ligands reduce the pathological cascade of Alzheimer's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets