Alzheimer's disease (AD), a leading cause of dementia worldwide, is a multifactorial neurodegenerative disorder characterized by amyloid-beta plaques, tauopathy, neuronal loss, neuro-inflammation, brain atrophy, and cognitive deficits. AD manifests as familial early-onset (FAD) with specific gene mutations or sporadic late-onset (LOAD) caused by various genetic and environmental factors. Numerous transgenic rodent models have been developed to understand AD pathology development and progression. The TgF344-AD rat model is a double transgenic model that carries two human gene mutations: APP with the Swedish mutation and PSEN-1 with delta exon 9 mutations. This model exhibits a complete repertoire of AD pathology in an age-dependent manner. This review summarizes multidisciplinary research insights gained from studying TgF344-AD rats in the context of AD pathology. We explore neuropathological findings; electrophysiological assessments revealing disrupted synaptic transmission, reduced spatial coding, network-level dysfunctions, and altered sleep architecture; behavioral studies highlighting impaired spatial memory; alterations in excitatory-inhibitory systems; and molecular and physiological changes in TgF344-AD rats emphasizing their age-related effects. Additionally, the impact of various interventions studied in the model is compiled, underscoring their role in bridging gaps in understanding AD pathogenesis. The TgF344-AD rat model offers significant potential in identifying biomarkers for early detection and therapeutic interventions, providing a robust platform for advancing translational AD research. Key words Alzheimer's disease, Transgenic AD models, TgF344-AD rats, Spatial coding.
- MeSH
- Alzheimerova nemoc * genetika patologie metabolismus MeSH
- amyloidový prekurzorový protein beta genetika metabolismus MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- modely nemocí na zvířatech * MeSH
- mozek patologie metabolismus MeSH
- potkani inbrední F344 MeSH
- potkani transgenní * MeSH
- presenilin-1 genetika MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
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.
- 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
During the past two decades, induced pluripotent stem cells (iPSCs) have been widely used to study human neural development and disease. Especially in the field of Alzheimer's disease (AD), remarkable effort has been put into investigating molecular mechanisms behind this disease. Then, with the advent of 3D neuronal cultures and cerebral organoids (COs), several studies have demonstrated that this model can adequately mimic familial and sporadic AD. Therefore, we created an AD-CO model using iPSCs derived from patients with familial AD forms and explored early events and the progression of AD pathogenesis. Our study demonstrated that COs derived from three AD-iPSC lines with PSEN1(A246E) or PSEN2(N141I) mutations developed the AD-specific markers in vitro, yet they also uncover tissue patterning defects and altered development. These findings are complemented by single-cell sequencing data confirming this observation and uncovering that neurons in AD-COs likely differentiate prematurely.
BACKGROUND: Prolactin-releasing peptide (PrRP) is a potential drug for the treatment of obesity and associated Type 2 Diabetes Mellitus (T2DM) due to its strong anorexigenic and antidiabetic properties. In our recent study, the lipidized PrRP analog palm11-PrRP31 was proven to exert beneficial effects in APP/PS1 mice, a model of Alzheimer ́s Disease (AD)-like amyloid-β (Aβ) pathology, reducing the Aβ plaque load, microgliosis and astrocytosis in the hippocampus and cortex. OBJECTIVE: In this study, we focused on the neuroprotective and anti-inflammatory effects of palm11-PrRP31 and its possible impact on synaptogenesis in the cerebellum of APP/PS1 mice, because others have suggested that cerebellar Aβ plaques contribute to cognitive deficits in AD. METHODS: APP/PS1 mice were treated subcutaneously with palm11-PrRP31 for 2 months, then immunoblotting and immunohistochemistry were used to quantify pathological markers connected to AD, compared to control mice. RESULTS: In the cerebella of 8 months old APP/PS1 mice, we found widespread Aβ plaques surrounded by activated microglia detected by ionized calcium-binding adapter molecule (Iba1), but no increase in astrocytic marker Glial Fibrillary Acidic Protein (GFAP) compared to controls. Interestingly, no difference in both presynaptic markers syntaxin1A and postsynaptic marker spinophilin was registered between APP/PS1 and control mice. Palm11-PrRP31 treatment significantly reduced the Aβ plaque load and microgliosis in the cerebellum. Furthermore, palm11-PrRP31 increased synaptogenesis and attenuated neuroinflammation and apoptosis in the hippocampus of APP/PS1 mice. CONCLUSION: These results suggest palm11-PrRP31 is a promising agent for the treatment of neurodegenerative disorders.
- MeSH
- Alzheimerova nemoc * metabolismus MeSH
- amyloidní beta-protein metabolismus MeSH
- amyloidní plaky patologie MeSH
- amyloidový prekurzorový protein beta genetika metabolismus MeSH
- diabetes mellitus 2. typu * MeSH
- hormon uvolňující prolaktin metabolismus farmakologie MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- mozeček MeSH
- myši transgenní MeSH
- myši MeSH
- presenilin-1 genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Peripheral infections followed by systemic inflammation may contribute to the onset of Alzheimer`s disease (AD) and accelerate the disease progression later in life. Yet, the impact of systemic inflammation on the plasma and brain tissue metabolome and lipidome in AD has not been investigated. In this study, targeted metabolomic and untargeted lipidomic profiling experiments were performed on the plasma, cortices, and hippocampi of wild-type (WT) mice and transgenic APdE9 mice after chronic lipopolysaccharide (LPS) treatment, as well as saline-treated APdE9 mice. The lipidome and the metabolome of these mice were compared to saline-treated WT animals. In the brain tissue of all three models, the lipidome was more influenced than the metabolome. The LPS-treated APdE9 mice had the highest number of changes in brain metabolic pathways with significant alterations in levels of lysine, myo-inositol, spermine, phosphocreatine, acylcarnitines and diacylglycerols, which were not observed in the saline-treated APdE9 mice. In the WT mice, the effect of the LPS administration on metabolome and lipidome was negligible. The study provided exciting information about the biochemical perturbations due to LPS-induced inflammation in the transgenic AD model, which can significantly enhance our understanding of the role of systemic inflammation in AD pathogenesis.
- MeSH
- Alzheimerova nemoc metabolismus MeSH
- amyloidní beta-protein metabolismus MeSH
- amyloidový prekurzorový protein beta genetika imunologie metabolismus MeSH
- hipokampus metabolismus MeSH
- lipidomika metody MeSH
- metabolom MeSH
- metabolomika metody MeSH
- modely nemocí na zvířatech MeSH
- mozek metabolismus MeSH
- myši inbrední C57BL MeSH
- myši transgenní MeSH
- myši MeSH
- presenilin-1 metabolismus MeSH
- zánět metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Increased levels of the pathogenic amyloid β-peptide (Aβ), released from its precursor by the transmembrane protease γ-secretase, are found in Alzheimer disease (AD) brains. Interestingly, monoamine oxidase B (MAO-B) activity is also increased in AD brain, but its role in AD pathogenesis is not known. Recent neuroimaging studies have shown that the increased MAO-B expression in AD brain starts several years before the onset of the disease. Here, we show a potential connection between MAO-B, γ-secretase and Aβ in neurons. METHODS: MAO-B immunohistochemistry was performed on postmortem human brain. Affinity purification of γ-secretase followed by mass spectrometry was used for unbiased identification of γ-secretase-associated proteins. The association of MAO-B with γ-secretase was studied by coimmunoprecipitation from brain homogenate, and by in-situ proximity ligation assay (PLA) in neurons as well as mouse and human brain sections. The effect of MAO-B on Aβ production and Notch processing in cell cultures was analyzed by siRNA silencing or overexpression experiments followed by ELISA, western blot or FRET analysis. Methodology for measuring relative intraneuronal MAO-B and Aβ42 levels in single cells was developed by combining immunocytochemistry and confocal microscopy with quantitative image analysis. RESULTS: Immunohistochemistry revealed MAO-B staining in neurons in the frontal cortex, hippocampus CA1 and entorhinal cortex in postmortem human brain. Interestingly, the neuronal staining intensity was higher in AD brain than in control brain in these regions. Mass spectrometric data from affinity purified γ-secretase suggested that MAO-B is a γ-secretase-associated protein, which was confirmed by immunoprecipitation and PLA, and a neuronal location of the interaction was shown. Strikingly, intraneuronal Aβ42 levels correlated with MAO-B levels, and siRNA silencing of MAO-B resulted in significantly reduced levels of intraneuronal Aβ42. Furthermore, overexpression of MAO-B enhanced Aβ production. CONCLUSIONS: This study shows that MAO-B levels are increased not only in astrocytes but also in pyramidal neurons in AD brain. The study also suggests that MAO-B regulates Aβ production in neurons via γ-secretase and thereby provides a key to understanding the relationship between MAO-B and AD pathogenesis. Potentially, the γ-secretase/MAO-B association may be a target for reducing Aβ levels using protein-protein interaction breakers.
- MeSH
- Alzheimerova nemoc metabolismus patologie MeSH
- amyloidní beta-protein metabolismus MeSH
- axony metabolismus MeSH
- dendrity metabolismus MeSH
- krysa rodu rattus MeSH
- lidé středního věku MeSH
- lidé MeSH
- malá interferující RNA genetika metabolismus MeSH
- molekulární modely MeSH
- monoaminoxidasa genetika metabolismus MeSH
- mozek metabolismus patologie MeSH
- myši MeSH
- neurony metabolismus ultrastruktura MeSH
- presenilin-1 genetika MeSH
- receptory N-methyl-D-aspartátu metabolismus MeSH
- regulace genové exprese genetika MeSH
- sekretasy metabolismus MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- synapse metabolismus MeSH
- transfekce MeSH
- transformované buněčné linie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
We report a 44-year-old woman, with a family history of early-onset dementia, presenting with primary progressive aphasia. This clinically variable syndrome has multiple underlying pathologies, and correlations between clinical manifestations and postmortem neuropathologic findings are controversial. Our patient suffered worsening language impairment with major word-finding difficulties but preserved comprehension. She also developed episodic memory impairment. Her condition progressed to dementia with behavioral changes. Magnetic resonance imaging showed early left perisylvian and bitemporal atrophy. The patient died shortly afterward from colon cancer. Neuropathologic examination revealed advanced early-onset Alzheimer and Lewy body disease, plus a clinically nonrelevant metastasis of her colon cancer in her left parietal lobe. Genetic examination revealed a p.Glu184Asp mutation in the presenilin1 gene. Our findings confirm the importance of a thorough appreciation for the clinical and neuropathologic correlations in patients with atypical neurodegenerative dementias.
- MeSH
- Alzheimerova nemoc komplikace diagnóza genetika patologie MeSH
- demence s Lewyho tělísky komplikace diagnóza genetika patologie MeSH
- dospělí MeSH
- fatální výsledek MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mozek patologie MeSH
- neurity patologie MeSH
- neurofibrilární klubka patologie MeSH
- neuropsychologické testy MeSH
- presenilin-1 genetika MeSH
- primární progresivní afázie diagnóza etiologie patologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
Transgenic APPswe/PS1dE9 mice modeling Alzheimer's disease demonstrate ongoing accumulation of β-amyloid fragments resulting in formation of amyloid plaques that starts at the age of 4-5 months. Buildup of β-amyloid fragments is accompanied by impairment of muscarinic transmission that becomes detectable at this age, well before the appearance of cognitive deficits that manifest around the age of 12 months. We have recently demonstrated that long-term feeding of trangenic mice with specific isocaloric fish oil-based diets improves specific behavioral parameters. Now we report on the influence of short-term feeding (3 weeks) of three isocaloric diets supplemented with Fortasyn (containing fish oil and ingredients supporting membrane renewal), the plant sterol stigmasterol together with fish oil, and stigmasterol alone on markers of cholinergic neurotransmission in the hippocampus of 5-month-old transgenic mice and their wild-type littermates. Transgenic mice fed normal diet demostrated increase in ChAT activity and attenuation of carbachol-stimulated GTP-γ(35)S binding compared to wild-type mice. None of the tested diets compared to control diet influenced the activities of ChAT, AChE, BuChE, muscarinic receptor density or carbachol-stimulated GTP-γ(35)S binding in wild-type mice. In contrast, all experimental diets increased the potency of carbachol in stimulating GTP-γ(35)S binding in trangenic mice to the level found in wild-type animals. Only the Fortasyn diet increased markers of cholinergic synapses in transgenic mice. Our data demonstrate that even short-term feeding of transgenic mice with chow containing specific lipid-based dietary supplements can influence markers of cholinergic synapses and rectify impaired muscarinic signal transduction that develops in transgenic mice.
- MeSH
- Alzheimerova nemoc dietoterapie patofyziologie MeSH
- amyloidový prekurzorový protein beta genetika metabolismus MeSH
- dietní tuky aplikace a dávkování MeSH
- hipokampus patofyziologie MeSH
- kaspasa 8 metabolismus MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C3H MeSH
- myši inbrední C57BL MeSH
- myši transgenní MeSH
- nervový přenos fyziologie MeSH
- presenilin-1 genetika metabolismus MeSH
- receptory muskarinové metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Presenile dementia may be caused by a variety of different genetic conditions such as familial Alzheimer's disease, prion disease as well as several hereditary metabolic disorders including adult onset neuronal ceroid lipofuscinosis. We report a multigenerational family with autosomal dominant presenile dementia harboring a cerebellar phenotype. Longitudinal clinical work-up in affected family members revealed ataxia accompanied by progressive cognitive decline, rapid loss of global cognition, memory, visuospatial and frontal-executive functions accompanied by progressive motor deterioration and early death. Linkage analysis and exome sequencing identified the p.S170F mutation of Presenilin 1 in all affected individuals, which is known to be associated with very early onset Alzheimer's disease. Additional search for potentially modifying variants revealed in all affected individuals of the third generation a paternally inherited variant p.A58V (rs17571) of Cathepsin D which is considered an independent risk factor for Alzheimer's disease. Involvement of cerebellar and brainstem structures leading to functional decortication in addition to rapid progressive presenile dementia in this PSEN1 family may therefore indicate an epistatic effect of the p.A58V Cathepsin D variant on the deleterious course of this disease.
- MeSH
- Alzheimerova nemoc diagnóza genetika MeSH
- dospělí MeSH
- genetická variace * genetika MeSH
- kathepsin D * genetika MeSH
- lidé MeSH
- mutace * genetika MeSH
- nemoci mozečku * diagnóza genetika MeSH
- presenilin-1 * genetika MeSH
- rodokmen MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
Alzheimerova demence je nejčastější demence u pacientů ve starším věku. V některých rodinách může být geneticky podmíněna. Naše kazuistika ukazuje případ 43letého muže, v jehož rodině se vyskytlo dalších šest členů rodiny s manifestací demence ve věku 40–50 let. Genetickým vyšetřením byla u pacienta prokázána patogenní mutace c.415A>G (p.M139V) v exonu 5 genu PSEN1 v heterozygotním stavu. Stejná mutace byla zjištěna u demencí postiženého bratrance. V rodině tak byla potvrzena hereditární predispozice k časné formě Alzheimerovy demence s autozomálně dominantní dědičností na molekulární úrovni. Vývoj onemocnění byl u pacienta sledován po dobu osmi let. Postupně dochází k deterioraci kognitivních funkcí a vývoji atrofických změn mozku dle magnetické rezonance. Obdobné změny jsou pozorovány u jeho bratrance. Genetické vyšetřování v rodinách zasažených demencí může být do budoucna důležité především pro možnost včasné léčby pacientů v riziku.
Alzheimer's disease is the most frequently diagnosed form of dementia in older patients. In some families, a tendency to this disorder may be inherited. This case report describes a 43-year-old man in the family of whom are six other members suffering from dementia, between the ages of 40 and 50 years. Molecular genetic analysis revealed a pathogenic c.415A>G (p.M139V) mutation in exon 5 of the PSEN1 gene in the heterozygous state. The same mutation was found in a cousin who has also suffered from dementia since the age of 45. Thus a hereditary predisposition to the early-onset form of Alzheimer's disease was confirmed in this family at a molecular level. The patient was followed up for eight years. Gradual deterioration of cognitive functions and progression of brain atrophy was observed on MRI. Similar changes were observed in the cousin. Genetic testing in families suffering from dementia may be important in the future, together with the development of drugs capable of preventing the disease.
- Klíčová slova
- Alzheimerova demence, hereditární onemocnění, genová mutace,
- MeSH
- Alzheimerova nemoc diagnóza etiologie genetika MeSH
- atrofie diagnóza MeSH
- chronické poškození mozku diagnóza etiologie genetika MeSH
- demence diagnóza epidemiologie genetika MeSH
- diferenciální diagnóza MeSH
- dospělí MeSH
- genetické nemoci vrozené MeSH
- genetické testování metody využití MeSH
- kognitivní poruchy diagnóza etiologie MeSH
- lidé MeSH
- magnetická rezonanční tomografie metody využití MeSH
- presenilin-1 genetika izolace a purifikace MeSH
- presenilin-2 genetika izolace a purifikace MeSH
- progrese nemoci MeSH
- sekretasy genetika izolace a purifikace MeSH
- zárodečné mutace genetika MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
