Alzheimer's disease (AD) is the most common form of dementia. Characterized by progressive neurodegeneration, AD typically begins with mild cognitive decline escalating to severe impairment in communication and responsiveness. It primarily affects cerebral regions responsible for cognition, memory, and language processing, significantly impeding the functional independence of patients. With nearly 50 million dementia cases worldwide, a number expected to triple by 2050, the need for effective treatments is more urgent than ever. Recent insights into the association between obesity, type 2 diabetes mellitus, and neurodegenerative disorders have led to the development of promising treatments involving antidiabetic and anti-obesity agents. One such novel promising candidate for addressing AD pathology is a lipidized analogue of anorexigenic peptide called prolactin-releasing peptide (palm11-PrRP31). Interestingly, anorexigenic and orexigenic peptides have opposite effects on food intake regulation, however, both types exhibit neuroprotective properties. Recent studies have also identified ghrelin, an orexigenic peptide, as a potential neuroprotective agent. Hence, we employed both anorexigenic and orexigenic compounds to investigate the common mechanisms underpinning their neuroprotective effects in a triple transgenic mouse model of AD (3xTg-AD mouse model) combining amyloid-beta (Aβ) pathology and Tau pathology, two hallmarks of AD. We treated 3xTg-AD mice for 4 months with two stable lipidized anorexigenic peptide analogues - palm11-PrRP31, and liraglutide, a glucagon-like peptide 1 (GLP-1) analogue - as well as Dpr3-ghrelin, a stable analogue of the orexigenic peptide ghrelin, and using the method of immunohistochemistry and western blot demonstrate the effects of these compounds on the development of AD-like pathology in the brain. Palm11-PrRP31, Dpr3-ghrelin, and liraglutide reduced intraneuronal deposits of Aβ plaque load in the hippocampi and amygdalae of 3xTg-AD mice. Palm11-PrRP31 and Dpr3-ghrelin reduced microgliosis in the hippocampi, amygdalae, and cortices of 3xTg-AD mice. Palm11-PrRP31 and liraglutide reduced astrocytosis in the amygdalae of 3xTg-AD mice. We propose that these peptides are involved in reducing inflammation, a common mechanism underlying their therapeutic effects. This is the first study to demonstrate improvements in AD pathology following the administration of both orexigenic and anorexigenic compounds, highlighting the therapeutic potential of food intake-regulating peptides in neurodegenerative disorders.

• Klíčová slova
• 3xTg-AD mice, Alzheimer’s disease, Anorexigenic peptide analogues, Neuroinflammation, Orexigenic peptide analogues,
• MeSH
• Alzheimerova nemoc * farmakoterapie   metabolismus   patologie   MeSH
• amyloidní beta-protein metabolismus   MeSH
• amyloidový prekurzorový protein beta genetika   metabolismus   MeSH
• ghrelin farmakologie   analogy a deriváty   terapeutické užití   metabolismus   MeSH
• hormon uvolňující prolaktin * analogy a deriváty   farmakologie   MeSH
• lidé MeSH
• liraglutid farmakologie   terapeutické užití   MeSH
• modely nemocí na zvířatech * MeSH
• myši inbrední C57BL MeSH
• myši transgenní * MeSH
• myši MeSH
• neuroprotektivní látky farmakologie   terapeutické užití   MeSH
• neurozánětlivé nemoci farmakoterapie   metabolismus   MeSH
• presenilin-1 genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• amyloidní beta-protein MeSH
• amyloidový prekurzorový protein beta MeSH
• ghrelin MeSH
• hormon uvolňující prolaktin * MeSH
• liraglutid MeSH
• neuroprotektivní látky MeSH
• presenilin-1 MeSH

Alzheimer's disease (AD) is a progressive brain disorder characterized by extracellular amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles formed by hyperphosphorylated Tau protein and neuroinflammation. Previous research has shown that obesity and type 2 diabetes mellitus, underlined by insulin resistance (IR), are risk factors for neurodegenerative disorders. In this study, obesity-induced peripheral and central IR and inflammation were studied in relation to AD-like pathology in the brains and periphery of APP/PS1 mice, a model of Aβ pathology, fed a high-fat diet (HFD). APP/PS1 mice and their wild-type controls fed either a standard diet or HFD were characterized at the ages of 3, 6 and 10 months by metabolic parameters related to obesity via mass spectroscopy, nuclear magnetic resonance, immunoblotting and immunohistochemistry to quantify how obesity affected AD pathology. The HFD induced substantial peripheral IR leading to central IR. APP/PS1-fed HFD mice had more pronounced IR, glucose intolerance and liver steatosis than their WT controls. The HFD worsened Aβ pathology in the hippocampi of APP/PS1 mice and significantly supported both peripheral and central inflammation. This study reveals a deleterious effect of obesity-related mild peripheral inflammation and prediabetes on the development of Aβ and Tau pathology and neuroinflammation in APP/PS1 mice.

• Klíčová slova
• APP/PS1, Alzheimer’s disease, amyloid-β, glucose intolerance, inflammation, insulin resistance, neuroinflammation, obesity, tau protein,
• MeSH
• Alzheimerova nemoc * etiologie   MeSH
• amyloidní beta-protein MeSH
• diabetes mellitus 2. typu * MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• inzulinová rezistence * MeSH
• myši MeSH
• neurozánětlivé nemoci MeSH
• zánět MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• amyloidní beta-protein MeSH