Liraglutide Reduces Vascular Damage, Neuronal Loss, and Cognitive Impairment in a Mixed Murine Model of Alzheimer’s Disease and Type 2 Diabetes

Abstract

Alzheimer’s disease is the most common form of dementia, and epidemiological studies support that type 2 diabetes (T2D) is a major contributor. The relationship between both diseases and the fact that Alzheimer’s disease (AD) does not have a successful treatment support the study on antidiabetic drugs limiting or slowing down brain complications in AD. Among these, liraglutide (LRGT), a glucagon-like peptide-1 agonist, is currently being tested in patients with AD in the Evaluating Liraglutide in Alzheimer’s Disease (ELAD) clinical trial. However, the effects of LRGT on brain pathology when AD and T2D coexist have not been assessed. We have administered LRGT (500 μg/kg/day) to a mixed murine model of AD and T2D (APP/PS1xdb/db mice) for 20 weeks. We have evaluated metabolic parameters as well as the effects of LRGT on learning and memory. Postmortem analysis included assessment of brain amyloid-β and tau pathologies, microglia activation, spontaneous bleeding and neuronal loss, as well as insulin and insulin-like growth factor 1 receptors. LRGT treatment reduced glucose levels in diabetic mice (db/db and APP/PS1xdb/db) after 4 weeks of treatment. LRGT also helped to maintain insulin levels after 8 weeks of treatment. While we did not detect any effects on cortical insulin or insulin-like growth factor 1 receptor m-RNA levels, LRGT significantly reduced brain atrophy in the db/db and APP/PS1xdb/db mice. LRGT treatment also rescued neuron density in the APP/PS1xdb/db mice in the proximity (p = 0.008) far from amyloid plaques (p < 0.001). LRGT reduced amyloid plaque burden in the APP/PS1 animals (p < 0.001), as well as Aβ aggregates levels (p = 0.046), and tau hyperphosphorylation (p = 0.009) in the APP/PS1xdb/db mice. Spontaneous bleeding was also ameliorated in the APP/PS1xdb/db animals (p = 0.012), and microglia burden was reduced in the proximity of amyloid plaques in the APP/PS1 and APP/PS1xdb/db mice (p < 0.001), while microglia was reduced in areas far from amyloid plaques in the db/db and APP/PS1xdb/db mice (p < 0.001). This overall improvement helped to rescue cognitive impairment in AD-T2D mice in the new object discrimination test (p < 0.001) and Morris water maze (p < 0.001). Altogether, our data support the role of LRGT in reduction of associated brain complications when T2D and AD occur simultaneously, as regularly observed in the clinical arena.

Current Insights on the Use of Insulin and the Potential Use of Insulin Mimetics in Targeting Insulin Signalling in Alzheimer’s Disease

“…This GLP-1 agonist has also been shown to reverse memory impairment and synaptic loss in Aβ mouse models [ 106 ] with similar findings in nonhuman primate models [ 101 ]. Similar findings were observed in AD mouse models in the presence of T2D [ 107 , 108 ], suggesting multiple mechanisms underlying liraglutide’s neuroprotective benefits. Similar findings have been reported on another GLP-1 agonist, exendin-4, as it has been shown to increase brain insulin synthesis [ 109 ], to restore cerebral insulin signalling [ 110 ], to attenuate Aβ and tau pathology as well as neuroinflammation [ 111 , 112 , 113 ] and to improve cognition [ 113 ].…”

Anti-Inflammatory Effects of GLP-1 Receptor Activation in the Brain in Neurodegenerative Diseases

“…Liraglutide reduces by 40–50% the overall β-amyloid plaque count and dense-core plaque numbers, and by 50% the number of activated microglia in the cortex [ 161 ] and the hippocampus [ 162 ] of APP/PS1 mice. Liraglutide also exerts neuroprotective effects and reduces cortical microglia burden and number in the proximity of amyloid plaques in APP/PS1x db / db and APPswe/PS1dE9 mice [ 163 , 164 ]. It also reduces astrocytosis in APPswe/PS1dE9 mice [ 164 ].…”

The mechanism and efficacy of GLP-1 receptor agonists in the treatment of Alzheimer’s disease

“…Cerebral microvascular impairments occurring in AD may reduce Aβ clearance. Some studies found liraglutide reduced incidence of cerebral microanuerysms and leakage ( 209 , 210 ).…”