Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, the accumulation of plaques (which are aggregated forms of beta amyloid protein) and tangles (which are tau proteins that are altered
in shape by the addition of too many phosphate atoms, a process known as hyperphosphorylation). In addition, there are several other neuropathological markers for AD, including neuroinflammation, which is the accumulation of proteins
and glial cells that signal pathological processing in the brain. Increasing evidence suggests that metabolic dysfunction, particularly insulin resistance, plays a crucial role in AD pathogenesis. Liraglutide, a glucagon-like peptide-1
receptor (GLP-1R) agonist used to treat Type II diabetes, has demonstrated neuroprotective properties, including the enhancement of insulin signaling and the reduction of amyloid pathology and neuroinflammation.
This study will investigate the potential therapeutic effects of liraglutide in mitigating AD-related cognitive and neuropathological deficits using 5xFAD transgenic mice (which are mice that have five human mutations associated with AD),
modeling a familial (or genetic) form of AD. Previous work with this model has suggested that it might prevent plaques in 5xFAD mice at a relatively early age of 3 months in these mice, a time period that precedes severe memory deficits.
This study will compare liraglutide treatment in 3-month-old and in 6-month-old 5xFAD mice and wild-type (WT) which are normal mice with no transgenes. In addition, sex differences will be assessed, so equal numbers of male and female
5xFAD mice and WT mice will be assessed.
Mice will be divided into eight groups of six mice:
- (1) 3-month-old male 5xFAD;
- (2) 3-month-old female 5xFAD;
- (3) 3-month-old male WT;
- (4) 3-month-old female WT;
- (5) 6-month-old male 5xFAD;
- (6) 6-month-old female 5xFAD;
- (7) 6-month-old male WT
- and (8) 6-month-old female WT.
All mice will receive daily intraperitoneal injections (which are injections by needle into the peritoneal cavity just below the rib cage) of either liraglutide (25 nM/kg) or vehicle (which is phosphate buffer saline without the liraglutide)
for 36 days.
Cognitive and behavioral functions will be assessed in the final week of treatment using the open-field test (to assess spontaneous motor function and anxiety-like behavior), novel object recognition (memory), and passive avoidance (learning
and memory retention) tests. Following behavioral assessments, brain and peripheral tissues will be collected and analyzed through immunohistochemistry (which is a means of identifying proteins with fluorescent tags) and Western blotting
(a means of measuring key protein markers). For immunohistochemistry, fluorescently tagged antibodies are used to measure neuroinflammation (GFAP, Iba1), amyloid pathology (6E10), neuronal integrity (Fluoro-Jade B), and metabolic signaling
(AMPK/pAMPK, mTOR, IDE, IR/pIR, GSK3B/pGSK3B, Akt/pAkt) in the brains and heart, pancreas, liver, spleen, and kidneys. Correlating the results of the behavioral assessments with the biological and biochemical analyses should provide
a comprehensive understanding of how liraglutide might exert its ameliorative effects in this mouse model of AD.
Specific Aims
Aim 1
To assess the cognitive and behavioral effects of liraglutide. Behavioral tests will measure memory, anxiety, and learning to determine whether liraglutide improves cognitive function in AD models. Hypothesis: Liraglutide will enhance cognitive performance and reduce anxiety-like behaviors in treated mice.
Aim 2
To examine metabolic and neurodegenerative markers. Western blot analysis of brain and peripheral tissues will evaluate key proteins related to insulin signaling, inflammation, and amyloid accumulation. Hypothesis: Liraglutide will improve metabolic function and reduce pathological protein expression associated with AD.
Aim 3
To investigate neuroinflammation and neurodegeneration. Immunohistochemical staining of brain tissue will assess gliosis, amyloid deposition, and neuronal loss. Hypothesis: Liraglutide will
reduce neuroinflammatory markers and neuronal damage in treated mice.
Interdisciplinary Research Components (excerpt)
This study embodies a robust interdisciplinary approach by integrating psychology, biology, and biochemistry to investigate the systemic and neurophysiological effects of liraglutide on Alzheimer’s disease (AD) and diabetes-related cognitive
dysfunction. The central research question—how liraglutide mitigates cognitive decline and metabolic dysfunction in both a genetically predisposed and sporadic model of AD—requires multiple disciplinary perspectives to be fully addressed.
This research integrates methods from each of these disciplines to create a comprehensive assessment framework: behavioral testing evaluates cognitive function and psychological outcomes (psychology), histological staining characterizes
neuroinflammatory and degenerative processes (biology), and Western blotting elucidates underlying molecular mechanisms (biochemistry). Each discipline’s methodologies complement and strengthen the overall study, addressing individual
limitations; behavioral tests can indicate dysfunction but not causality, whereas biochemical assays provide mechanistic insights but lack a functional context.
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