The Novel DA–CH3 Dual Incretin Restores Endoplasmic Reticulum Stress and Autophagy Impairments to Attenuate Alzheimer-Like Pathology and Cognitive Decrements in the APPSWE/PS1ΔE9 Mouse Model

Abstract

Alzheimer's disease (AD) afflicts more than 46.8 million people worldwide, with a newly diagnosed case every 3 seconds and no remission in the disease progression. The discovery of disease-modifying drugs is now on the summit of the neuropharmacological research priorities. The long-lasting derivatives of the insulinotropic incretin hormones-glucagonlike peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)-have repeatedly been shown to cross the blood-brain barrier and counteract an array of deleterious effects across a range of experimental models of neuronal degeneration. Clinical trials for the efficacy of GLP-1 agonists in Alzheimer's and Parkinson's diseases have revealed beneficial effects of these anti-diabetic agents in halting neuronal degeneration progression. Herein, we examine whether the chronic treatment with the novel dual GLP-1/GIP receptor agonist DA-CH3 can restore the cognitive decline and AD-like cerebral pathology of the APP SWE /PS1 E9 mouse model at the age of 10 months old. We report that once-a-daily, eight-week intraperitoneal administration of 25 nmol/kg of the novel DA-CH3 dual-incretin analog rescues the spatial acquisition and memory impairments of this murine model that corresponds to the attenuation of the excessive plaque deposition, gliosis and synaptic damage in the APP SWE /PS1 E9 brain. The amelioration of the AD-related pathology reflects the resolution of the endoplasmic-reticulum stress and derailed autophagy that both lay downstream of the rectified Akt signaling. Collectively, our findings endorse the beneficial effects of the incretin-based therapeutic approaches for the neurotrophic support of the AD brain and for the first time associate the incretin-induced neuroprotection with the proteostasis machinery in vivo.

Suan-Zao-Ren Decoction ameliorates synaptic plasticity through inhibition of the Aβ deposition and JAK2/STAT3 signaling pathway in AD model of APP/PS1 transgenic mice

“…Author details 1 School of Basic Medicine, Hubei University of Chinese Medicine, Wuhan 430065, Hubei, China. 2 School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, Hubei, China.…”

“…Alzheimer's disease (AD) is a chronic degenerative illness in the brain and is one of the common kinds of dementia [1,2]. Based on the AD's World Report 2018, the patients with AD worldwide exceeded 47 million in 2018 [3].…”

“…With the growth of the aging population, the AD prevalence in the world is increasing rapidly. It is estimated that AD patients in the world will be more than 150 million by 2050 [2]. Currently, the drugs used for AD treatment are composed of Donepezil, rivastigmine, galanthamine and memantine [5,6].…”

<p>Qingxin kaiqiao fang ameliorates memory impairment and inhibits apoptosis in APP/PS1 double transgenic mice through the MAPK pathway</p>

“…AD is a devastating age-related neurodegenerative disorder that is the most common cause of dementia worldwide 2–4. According to the amyloid hypothesis, the deposition of aggregated Aβ in brain areas involved in cognitive function is assumed to initiate a pathological cascade resulting in neuronal dysfunction and death in AD 27,28.…”

Suan-Zao-Ren Decoction&nbsp;Ameliorate&nbsp;Synaptic Plasticity Through&nbsp;the Inhibition of JAK2/STAT3 Signaling Pathway&nbsp;in APP/PS1 Transgenic Mice

“…Alzheimer's disease (AD) is a chronic degenerative illness that occurs in the brain and is one of the common kinds of dementia [1,2]. Based on the AD's World Report 2018, the patients with AD around the world exceeded 47 million in 2018 [3].…”