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 credits: Marko Aliaksandr / Shutterstock
This is evident from a recent study published in the journal Biomedicine and pharmacotherapya 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 mainly affects older adults and leads to cognitive decline, memory loss, and reduced functional skills.
Despite significant advances in research, there is currently no cure and existing treatments only treat symptoms without halting disease progression. The prevalence of AD increases as the population ages, making it a critical public health problem.
Recent research suggests that glucagon-like peptide-1 (GLP-1) receptor agonists, including Semaglutide, exhibit neuroprotective potential in AD models by reducing inflammation, amyloid-beta (Aβ) accumulation, and tau hyperphosphorylation. These effects may be mediated through important 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 according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals in the study. Five-month-old male transgenic mice Amyloid Precursor Protein/Presenilin 1 (APP/PS1) 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-h 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 administered 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 ability with hidden platform trials and spatial memory assessments. The performances were recorded using video tracking systems.
Other behavioral tests, such as nest building behavior and active avoidance tests, were also administered to assess general cognitive skills and memory.
Tissue samples from treated mice were collected for biochemical analysis, including protein and ribonucleic acid (RNA) testing. Statistical analyzes were performed using SPSS and results were considered significant when P values were less than 0.05.
Study results
Semaglutide has been shown to improve learning and memory in APP/PS1 mice, which are known to exhibit cognitive decline and develop amyloid plaques by six months of age.
To assess the cognitive effects of Semaglutide, several behavioral tests were performed 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, indicating improved learning ability.
Similarly, in the Morris water maze test, the APP/PS1 model group showed longer latency to find the hidden platform, but Semaglutide-treated mice showed faster performance, indicating improvements in spatial learning and memory.
Semaglutide-treated mice also showed improvements in their daily functioning, as assessed by nest-building behavior. Mice treated with Semaglutide performed significantly better than untreated APP/PS1 mice at nest building, indicating that they are better able to perform daily activities.
Despite these cognitive improvements, 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 with WT mice.
Semaglutide treatment significantly reduced the amyloid plaque area and decreased the levels of both Aβ1–40 and Aβ1–42 in brain tissue.
Although Semaglutide reduced total Tau protein levels, the study noted that phosphorylated Tau levels (p-Tau) remained unchanged in the hippocampus, indicating that the reduction may mainly affect total Tau levels. These findings suggest that Semaglutide may reduce amyloid pathology and Tau accumulation in APP/PS1 mice.
In addition, Semaglutide was shown to reduce neuroinflammation by reducing the expression of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter 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 levels of BACE1, an enzyme involved in amyloid production, and found no significant changes in serum concentration after treatment, indicating that Semaglutide’s effects may not involve BACE1 modulation.
Finally, 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 new 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
In summary, behavioral analysis in mice showed improved cognitive skills, especially in the areas of 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 tissue.
In human organoid models, Semaglutide increased OXT expression and decreased p-Tau, Aβ, and GFAP levels. These effects appeared to be dose dependent, with higher concentrations of Semaglutide producing a more pronounced reduction in AD markers. These findings suggest that Semaglutide may exert its neuroprotective effects via the GLP-1 receptor and OXT interaction, highlighting the potential of OXT as a therapeutic target for AD.