GLP-1 Receptor Stimulation Reduces Amyloid-β Peptide Accumulation and Cytotoxicity in Cellular and Animal Models of Alzheimer's Disease

Abstract

Type 2 (T2) diabetes mellitus (DM) has been associated with an increased incidence of neurodegenerative disorders, including Alzheimer's disease (AD). Several pathological features are shared between diabetes and AD, including dysfunctional insulin signaling and a dysregulation of glucose metabolism. It has therefore been suggested that not only may the two conditions share specific molecular mechanisms but also that agents with proven efficacy in one may be useful against the other. Hence, the present study characterized the effects of a clinically approved long-acting analogue, exendin-4 (Ex-4), of the endogenous insulin releasing incretin, glucagon-like peptide-1 (GLP-1), on stress-induced toxicity in neuronal cultures and on amyloid-beta protein (Abeta) and tau levels in triple transgenic AD (3xTg-AD) mice with and without streptozocin (STZ)-induced diabetes. Ex-4 ameliorated the toxicity of Abeta and oxidative challenge in primary neuronal cultures and human SH-SY5Y cells in a concentration-dependent manner. When 11 to 12.5 month old female 3xTg AD mice were challenged with STZ or saline, and thereafter treated with a continuous subcutaneous infusion of Ex-4 or vehicle, Ex-4 ameliorated the diabetic effects of STZ in 3xTg-AD mice, elevating plasma insulin and lowering both plasma glucose and hemoglobin A1c (HbA1c) levels. Furthermore, brain levels of Abeta protein precursor and Abeta, which were elevated in STZ 3xTg-AD mice, were significantly reduced in Ex-4 treated mice. Brain tau levels were unaffected following STZ challenge, but showed a trend toward elevation that was absent following Ex-4 treatment. Together, these results suggest a potential value of Ex-4 in AD, particularly when associated with T2DM or glucose intolerance.

Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline

“…IR inhibition can thus greatly elevate extracellular Aβ oligomers. This downregulation in the internalization of Aβ may explain previously reported reductions in Aβ pathology seen in insulin-resistant neurons, animal models of AD, and diabetic humans after treatment with insulin plus antidiabetic agents (119) or the IR-sensitizing agents metformin (120) and glucagon-like peptide 1 (GLP-1) mimetics (121)(122)(123)(124)(125).…”

“…Metformin (120, 165) and 2 GLP-1 mimetics (121, 124, 125, 165, 166) are antidiabetic agents approved by the FDA without restriction; all have excellent safety profiles, readily cross the bloodbrain barrier, and raise insulin-induced IR and IRS-1 activation. These agents are all neuroprotectants (120,167,168) that reduce extracellular Aβ levels in cultures of insulin-resistant neurons (120,122) and in AD mouse models (122,124). In such mice, the GLP-1 mimetic liraglutide decreases oligomeric Aβ, neuritic plaque load, and microglial activation; elevates neurogenesis; restores LTP; and improves object recognition and spatial memory (124,169).…”

Potentials of incretin‐based therapies in dementia and stroke in type 2 diabetes mellitus

“…ICV‐infused (Val 8 )GLP‐1 or GIP reversed impairment of LTP induced by Aβ32, 33, 70. ICV‐infused liraglutide and peripherally‐administered exendin‐4 also enhanced LTP in an AD model31, and in a diabetes‐related AD model80. One study showed that peripherally‐administered D‐Ala 2 GIP facilitated synaptic plasticity in mice at an advanced state of AD81.…”

“…Neuronal cell line studies showed that exendin‐4 reduced the levels of Aβ80, other neuronal cell line studies found that exendin‐4 reduced levels of APP, but had no impact on Aβ levels42, 80. In rodent models of AD, peripherally‐administered geniposide and D‐Ala 2 GIP reduced levels of Aβ plaque load81, 83, 84, 85.…”

Management of diabetes and dementia

“…[35][36][37] Although there is a low risk of hypoglycaemia, the effects on weight loss and increasing satiety effects may not be beneficial in this cohort of patients where appetite may already be suppressed. Their limited use in moderate to severe renal impairment also restricts their benefit.…”