Semaglutide enhances cognitive abilities and reduces Alzheimer’s pathology in mice and human brain models

Research shows that Semaglutide not only improves memory and learning in Alzheimer’s models, but also reduces harmful plaques and proteins, while restoring the neuroprotective effects of oxytocin.

Study: Semaglutide ameliorates Alzheimer’s disease and restores oxytocin in APP/PS1 mice and human brain organoid models. Image Credit: Marko Aliaksandr / Shutterstock

In a recent study published in the journal Biomedicine & Pharmacotherapy, a group of researchers investigated the therapeutic effects of Semaglutide in Alzheimer’s Disease (AD) and identified its molecular targets in both mouse and human brain organoid models.

Background

AD is a global neurodegenerative disorder that primarily affects older adults, leading to cognitive decline, memory loss, and reduced functional abilities.

Despite significant advancements in research, there is currently no cure, and existing treatments only manage symptoms without halting disease progression. AD’s prevalence is increasing with the aging population, making it a critical public health concern.

Recent research suggests that glucagon-like peptide-1 (GLP-1) receptor agonists, including Semaglutide, show neuroprotective potential in AD models by reducing inflammation, amyloid-beta (Aβ) accumulation, and tau hyperphosphorylation. These effects may be mediated through key pathways such as the PI3K/Akt/mTOR signaling pathway, which is involved in cellular survival and neuroprotection. Further research is needed to confirm their therapeutic efficacy in humans.

About the study

All animal experiments were conducted following the National Institutes of Health Guide for the Care and Use of Laboratory Animals in the study. Five-month-old male Amyloid Precursor Protein/Presenilin 1 (APP/PS1) transgenic mice, bred from Prion Protein Promoter-human Amyloid Precursor Protein with K595N and M596L mutations (PrP-hAPPK595N/M596L) and Prion Protein Promoter-human Presenilin 1 with a deletion of exon 9 (PrP-hPS1dE9) transgenic lines, were used. Age-matched wild-type (WT) C57BL/6J mice served as controls. The animals were housed under controlled conditions with a 12-hour light/dark cycle and had ad libitum access to food and water.

APP/PS1 mice were randomly divided into three groups: vehicle-treated, Donepezil-treated, and Semaglutide-treated. Donepezil was administered orally, while Semaglutide was given subcutaneously for six months. WT mice received double-distilled water as controls.

To evaluate cognitive function, the Morris water maze and Barnes maze tests were used. These tests measured learning and memory abilities with hidden platform trials and spatial memory assessments. Performance was recorded using video tracking systems.

Other behavioral tests, such as nest-building behavior and active avoidance tests, were also performed to assess general cognitive and memory abilities.

Tissue samples from treated mice were collected for biochemical analysis, including protein and Ribonucleic Acid (RNA) assays. Statistical analyses were conducted using SPSS, and results were considered significant when P-values were less than 0.05.

Study results

Semaglutide was shown to improve learning ability and memory in APP/PS1 mice, which are known to exhibit cognitive decline and develop amyloid plaques by 6 months of age.

To assess the cognitive effects of Semaglutide, several behavioral tests were conducted on 6-month-old APP/PS1 mice after 3 and 6 months of treatment.

In the Barnes maze test, the untreated model mice took significantly longer to find the target box compared to WT mice, indicating cognitive impairment.

However, mice treated with Semaglutide or Donepezil showed improved performance, with shorter latencies to reach the target box, suggesting enhanced learning ability.

Similarly, in the Morris water maze test, the APP/PS1 model group displayed a longer latency to find the hidden platform, but Semaglutide-treated mice demonstrated faster performance, indicating improvements in spatial learning and memory.

Semaglutide-treated mice also demonstrated improvements in their daily functioning, as assessed by nest-building behavior. Mice treated with Semaglutide significantly outperformed untreated APP/PS1 mice in building nests, suggesting enhanced abilities in daily activities.

Despite these cognitive improvements, the memory performance during the retention phase of the Morris water maze test remained unchanged.

Semaglutide also reduced amyloid plaque burden and Tau protein levels in the brain tissues of APP/PS1 mice. Immunohistochemical analysis revealed that the untreated APP/PS1 mice had significantly larger amyloid plaques and higher levels of Aβ1–40 and Aβ1–42 proteins compared to WT mice.

Semaglutide treatment significantly decreased the amyloid plaque area and reduced the levels of both Aβ1–40 and Aβ1–42 in brain tissues.

Although Semaglutide reduced overall Tau protein levels, the study noted that phosphorylated Tau (p-Tau) levels remained unchanged in the hippocampus, indicating that the reduction may primarily affect total Tau levels. These findings suggest Semaglutide can reduce amyloid pathology and Tau accumulation in APP/PS1 mice.

Furthermore, Semaglutide was found to reduce neuroinflammation by decreasing the expression of the glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba1) in brain tissues, markers of astrocyte and microglia activation, respectively. This indicates that Semaglutide attenuates the neuroinflammatory response associated with AD.

The researchers also measured the levels of BACE1, an enzyme involved in amyloid production, and found no significant changes in its serum concentration after treatment, indicating that Semaglutide’s effects might not involve BACE1 modulation.

Lastly, RNA sequencing of hippocampal tissue from Semaglutide-treated mice revealed an upregulation of oxytocin (OXT) expression, which was significantly reduced in untreated APP/PS1 mice. This novel finding suggests that oxytocin may play a key role in the neuroprotective effects of Semaglutide and may interact with GLP-1 signaling pathways in the brain.

Conclusions

To summarize, behavioral analysis in mice demonstrated improved cognitive abilities, particularly in learning and memory. Biochemical assessments revealed a reduction in amyloid plaque deposition, modulation of Tau protein levels, and downregulation of GFAP and Iba1 in mouse brain tissues.

In human organoid models, Semaglutide increased OXT expression and reduced p-Tau, Aβ, and GFAP levels. These effects were found to be dose-dependent, with higher concentrations of Semaglutide yielding more pronounced reductions in AD markers. These findings suggest that Semaglutide may exert its neuroprotective effects through the GLP-1 receptor and OXT interaction, highlighting OXT’s potential as a therapeutic target for AD.