Liraglutide Has Anti-Inflammatory and Anti-Amyloid Properties in Streptozotocin-Induced and 5xFAD Mouse Models of Alzheimer’s Disease

Abstract

Recent clinical and epidemiological studies support the contention that diabetes mellitus (DM) is a strong risk factor for the development of Alzheimer’s disease (AD). The use of insulin cell toxin, streptozotocin (STZ), when injected into the lateral ventricles, develops an insulin resistant brain state (IRBS) and represents a non-transgenic, or sporadic AD model (SAD), with several AD-like neuropathological features. The present study explored the effects of an anti-diabetic drug, liraglutide (LIR), in reversing major pathological hallmarks in the prodromal disease stage of both the 5xFAD transgenic and SAD mouse models of AD. Three-month-old 5xFAD and age-matched wild type mice were given a single intracerebroventricular (i.c.v) injection of STZ or vehicle (saline) and were subsequently treated with LIR, intraperitoneally (IP), once a day for 30 days. The extent of neurodegeneration, Aβ plaque load, and key proteins associated with the insulin signaling pathways were measured using Western blot and neuroinflammation (via immunohistological assays) in the cortical and hippocampal regions of the brain were assessed following a series of behavioral tests used to measure cognitive function after LIR or vehicle treatments. Our results indicated that STZ significantly increased neuroinflammation, Aβ plaque deposition and disrupted insulin signaling pathway, while 25 nmol/kg LIR, when injected IP, significantly decreased neuroinflammatory responses in both SAD and 5xFAD mice before significant cognitive changes were observed, suggesting LIR can reduce early neuropathology markers prior to the emergence of overt memory deficits. Our results indicate that LIR has neuroprotective effects and has the potential to serve as an anti-inflammatory and anti-amyloid prophylactic therapy in the prodromal stages of AD.

Tart Cherry Extract and Omega Fatty Acids Reduce Behavioral Deficits and Gliosis in the 5xFAD Mouse Model of Alzheimer’s Disease

“…The novel object recognition (NOR) task allows for the assessment of recognition memory in an environment with minimal stress [ 22 , 25 , 26 , 27 ]. We have published details of NOR procedure [ 24 ].…”

Immunotherapies for Neurodegenerative Diseases

“…Despite GLP-1 agonists and PPARγ agonists being primarily anti-diabetic drugs, recent findings indicate that these molecules execute neuroprotective and anti-inflammatory functions, which alleviate symptoms of AD and PD as well as rescuing Akt-1 and m-TOR, and insulin signaling in the brain (79)(80)(81)(82)(83)(84).…”

“…Pre-clinically, PPARγ agonists have been shown to reduce neuroinflammation, Aβ-42 load, phosphorylated tau, and synaptophysin, ultimately enhancing spatial memory and motor function in AD mouse models (81)(82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93). Furthermore, two promising PPAR-γ agonists currently under phase II clinical trials, T3D-959 (NCT04251182), and Pioglitazone (NCT00982202), have proven their safety and tolerability among patients (94,95).…”

Divergent Effect of Central Incretin Receptors Inhibition in a Rat Model of Sporadic Alzheimer’s Disease

“…These features of AD can also be found in certain animal models, like the rat model, induced by intracerebroventricular streptozotocin (STZ-icv) [ 17 , 18 ]. Lately, incretin analogues have also been tested as possible therapeutic agents in the STZ-icv rat model of sAD [ 19 , 20 ], since STZ is considered a diabetogenic compound. Analogues of incretins showed a neuroprotective effect, reduction in Aβ deposition, decreased inflammatory response, enhancement of synaptic plasticity, hippocampal neurogenesis, long-term potentiation (LTP), prevention of hippocampal synapse loss and oxidative stress, and improvement of cognitive deficit in animal AD models [ 10 , 15 , 19 , 20 , 21 ].…”