The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non‐human primate model of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a devastating neurological disorder that still lacks an effective treatment, and this has stimulated an intense pursuit of disease‐modifying therapeutics. Given the increasingly recognized link between AD and defective brain insulin signaling, we investigated the actions of liraglutide, a glucagon‐like peptide‐1 (GLP‐1) analog marketed for treatment of type 2 diabetes, in experimental models of AD. Insulin receptor pathology is an important feature of AD brains that impairs the neuroprotective actions of central insulin signaling. Here, we show that liraglutide prevented the loss of brain insulin receptors and synapses, and reversed memory impairment induced by AD‐linked amyloid‐β oligomers (AβOs) in mice. Using hippocampal neuronal cultures, we determined that the mechanism of neuroprotection by liraglutide involves activation of the PKA signaling pathway. Infusion of AβOs into the lateral cerebral ventricle of non‐human primates (NHPs) led to marked loss of insulin receptors and synapses in brain regions related to memory. Systemic treatment of NHPs with liraglutide provided partial protection, decreasing AD‐related insulin receptor, synaptic, and tau pathology in specific brain regions. Synapse damage and elimination are amongst the earliest known pathological changes and the best correlates of memory impairment in AD. The results illuminate mechanisms of neuroprotection by liraglutide, and indicate that GLP‐1 receptor activation may be harnessed to protect brain insulin receptors and synapses in AD. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Neuroprotective Effects and Treatment Potential of Incretin Mimetics in a Murine Model of Mild Traumatic Brain Injury

“…We avoided anxiety symptoms following the injury by using short-term anesthesia at the time of the TBI impact induction, to ensure that animals were unaware of the procedure. Hence, untoward actions on either anxiety or motor activity cannot be considered confounds when evaluating liraglutide and twincretin mitigation of mTBI-induced cognitive impairments, and these positive actions are in line with prior reports regarding the cognitive alleviation provided by incretin analogs following an mTBI challenge (Rachmany et al, 2013;Li et al, 2015;Tamargo et al, 2017;Bader et al, 2019;Glotfelty et al, 2019), as well as in Alzheimer's disease models (Faivre and Holscher, 2013;Shi et al, 2017;Batista et al, 2018;Glotfelty et al, 2019). FIGURE 7 | mTBI results in a decline in p-PKA levels in ipsilateral cortex.…”

Adiponectin: The Potential Regulator and Therapeutic Target of Obesity and Alzheimer’s Disease

“…In an AD mice model, Val(8)GLP-1, liraglutide, and exidin-4 (GLP-1 analogs, well known for the upregulation of adiponectin) treatments rescued synaptic plasticity by preventing synaptic degradation, which is also correlated with the increased learning ability of new spatial tasks [ 155 , 156 , 157 , 158 ]. Several studies have also shown the beneficiary effect of GLP-1 analogs for AD [ 159 , 160 , 161 ].…”

CGRP Antagonists: Side Effects and Potential Parkinson’s Disease Development

“…[4][5][6] With regard to PD, studies reveal the neuroprotective effect of GLP-1 in PD pre-clinical models and state that the link between PD and type 2 diabetes mellitus is not clear and is possibly related to a common pathogenetic pathway that both diseases share or arises as a result of chronic hyperglycemia. 7 In 2005 Chung and colleagues proved that CGRP reduced MPP+ induced mitochondrial toxicity and protected a midbrain subpopulation of dopamine cells in vitro. 8 The researchers did not exclude a potential protective effect of the neuropeptide in adult dopamine neurons in vivo.…”

“…As shown by several studies, CGRP exerts metabolic effects through the induction of glucagon‐like‐peptide‐1 (GLP‐1) release, which in turn leads to insulin secretion reduction . With regard to PD, studies reveal the neuroprotective effect of GLP‐1 in PD pre‐clinical models and state that the link between PD and type 2 diabetes mellitus is not clear and is possibly related to a common pathogenetic pathway that both diseases share or arises as a result of chronic hyperglycemia …”