INTRODUCTION: Amyloid precursor protein (APP) undergoes striking changes following traumatic brain injury (TBI). Considering its role in the control of gene expression, we investigated whether APP regulates transcription and translation following TBI. METHODS: We assessed brain morphology (n = 4-9 mice/group), transcriptome (n = 3 mice/group), proteome (n = 3 mice/group), and behavior (n = 17-27 mice/group) of wild-type (WT) and APP knock-out (KO) mice either untreated or 10-weeks following TBI. RESULTS: After TBI, WT mice displayed transcriptional programs consistent with late stages of brain repair, hub genes were predicted to impact translation and brain proteome showed subtle changes. APP KO mice largely replicated this transcriptional repertoire, but showed no transcriptional nor translational response to TBI. DISCUSSION: The similarities between WT mice following TBI and APP KO mice suggest that developmental APP deficiency induces a condition reminiscent of late stages of brain repair, hampering the control of gene expression in response to injury. HIGHLIGHTS: 10-weeks after TBI, brains exhibit transcriptional profiles consistent with late stage of brain repair. Developmental APP deficiency maintains brains perpetually in an immature state akin to late stages of brain repair. APP responds to TBI by changes in gene expression at a transcriptional and translational level. APP deficiency precludes molecular brain changes in response to TBI.

• MeSH
• Amyloid beta-Protein Precursor * genetics   MeSH
• Disease Models, Animal MeSH
• Brain * metabolism   pathology   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Brain Injuries * metabolism   genetics   pathology   MeSH
• Proteome * metabolism   MeSH
• Proteomics MeSH
• Transcriptome * MeSH
• Brain Injuries, Traumatic * metabolism   genetics   pathology   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

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
• Alzheimer Disease * genetics   pathology   metabolism   MeSH
• Amyloid beta-Protein Precursor genetics   metabolism   MeSH
• Rats MeSH
• Humans MeSH
• Disease Models, Animal * MeSH
• Brain pathology   metabolism   MeSH
• Rats, Inbred F344 MeSH
• Rats, Transgenic * MeSH
• Presenilin-1 genetics   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review 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
• Alzheimer Disease * drug therapy   metabolism   pathology   MeSH
• Amyloid beta-Peptides metabolism   MeSH
• Amyloid beta-Protein Precursor genetics   metabolism   MeSH
• Ghrelin pharmacology   analogs & derivatives   therapeutic use   metabolism   MeSH
• Prolactin-Releasing Hormone * analogs & derivatives   pharmacology   MeSH
• Humans MeSH
• Liraglutide pharmacology   therapeutic use   MeSH
• Disease Models, Animal * MeSH
• Mice, Inbred C57BL MeSH
• Mice, Transgenic * MeSH
• Mice MeSH
• Neuroprotective Agents pharmacology   therapeutic use   MeSH
• Neuroinflammatory Diseases drug therapy   metabolism   MeSH
• Presenilin-1 genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: The hippocampal representation of space, formed by the collective activity of populations of place cells, is considered as a substrate of spatial memory. Alzheimer's disease (AD), a widespread severe neurodegenerative condition of multifactorial origin, typically exhibits spatial memory deficits among its early clinical signs before more severe cognitive impacts develop. OBJECTIVE: To investigate mechanisms of spatial memory impairment in a double transgenic rat model of AD. METHODS: In this study, we utilized 9-12-month-old double-transgenic TgF344-AD rats and age-matched controls to analyze the spatial coding properties of CA1 place cells. We characterized the spatial memory representation, assessed cells' spatial information content and direction-specific activity, and compared their population coding in familiar and novel conditions. RESULTS: Our findings revealed that TgF344-AD animals exhibited lower precision in coding, as evidenced by reduced spatial information and larger receptive zones. This impairment was evident in maps representing novel environments. While controls instantly encoded directional context during their initial exposure to a novel environment, transgenics struggled to incorporate this information into the newly developed hippocampal spatial representation. This resulted in impairment in orthogonalization of stored activity patterns, an important feature directly related to episodic memory encoding capacity. CONCLUSIONS: Overall, the results shed light on the nature of impairment at both the single-cell and population levels in the transgenic AD model. In addition to the observed spatial coding inaccuracy, the findings reveal a significantly impaired ability to adaptively modify and refine newly stored hippocampal memory patterns.

• MeSH
• Alzheimer Disease * physiopathology   MeSH
• Amyloid beta-Protein Precursor genetics   MeSH
• CA1 Region, Hippocampal physiopathology   MeSH
• Hippocampus physiopathology   MeSH
• Rats MeSH
• Humans MeSH
• Disease Models, Animal * MeSH
• Memory Disorders etiology   physiopathology   MeSH
• Rats, Inbred F344 MeSH
• Rats, Transgenic * MeSH
• Spatial Memory physiology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Vedecká obec postupne rozuzluje etiologické faktory a patogenetické mechanizmy neurodegeneratívnych ochorení. Z roka na rok pribúdajú dôkazy o čoraz väčšej sile genetického pozadia ako etiologického faktora. V našom príspevku integrujeme dve roviny pohľadu na genetiku Alzheimerovej choroby a príbuzných demencií. V prvej časti článku sumarizujeme súčasné poznatky o genetickom pozadí neurodegeneratívnych demencií s hlavným zameraním sa na Alzheimerovu chorobu. Okrem "klasických" kauzálnych génov a génov susceptibility prinášame prehľad vybraných "nových" génov, ktorých polymorfizmy môžu zvyšovať náchylnosť na Alzheimerovu chorobu. V druhej časti - Skúsenosti z jedného centra - prinášame pohľad na vývoj a súčasný koncept genetického testovania na I. neurologickej klinike v Bratislave. Predstavujeme panel génov pre demencie, ktorý v súčasnosti zahŕňa 45 génov zapojených do patogenézy Alzheimerovej choroby, frontotemporálnej demencie, Parkinsonovej choroby a zriedkavých demencií. V blízkej budúcnosti ho plánujeme rozšíriť na 150-génový panel a postupne kontinuálne aktualizovať. Rozsah genetického testovania, ktorý prinášame v tomto príspevku, sa vzťahuje hlavne na kliniky špecializované na demencie a špecializované centrá pre demencie. Načrtávame koncept, akým by sa mohlo testovanie uberať do budúcnosti na príklade konceptu testovania na našej I. neurologickej klinike. V každom prípade sa snažíme priblížiť problematiku aj ostatným neurologickým klinikám, oddeleniam a ambulanciám, ktoré sa rovnako môžu zapojiť do tohto systému, ak majú vhodných pacientov. Článok ukončujeme kapitolou o relativite súčasných poznatkov, ktorá odzrkadľuje turbulentnú tému genetiky Alzheimerovej choroby, ktorá sa neustále mení, rozširuje, aktualizuje a možno prinesie odpovede na množstvo v súčasnosti nezodpovedaných otázok.

The scientific community is gradually unraveling the etiological factors and pathogenetic mechanisms of neurodegenerative diseases. From year to year there is the robust evidence of the increasing power of the genetic background as an etiological factor. In our paper, we integrate two levels of insight into the genetics of Alzheimer's disease and related dementias. In the first part of the article, we summarize current knowledge about the genetic background of neurodegenerative dementias, with the main focus on Alzheimer's disease. In addition to "classic" causal genes and susceptibility genes, we provide an overview of selected "new" genes whose polymorphisms can increase susceptibility to Alzheimer's disease. In the second part - Experience from one center - we present an insight into the development and current concept of genetic testing at the I. Neurological Clinic. We present a dementia gene panel that currently includes 45 genes involved in the pathogenesis of Alzheimer's disease, Frontotemporal dementia, Parkinson's disease and rare dementias. In the near future, we plan to expand it to a 150 gene panel and gradually update it continuously. The scope of genetic testing that we present in this manuscript mainly applies to dementia clinics and dementia centers. We outline the concept of how testing should proceed in the future using the example of the testing concept at our I. Neurological Clinic. In any case, we are trying to bring this issue closer to other neurological clinics, departments and outpatient clinics, which can also join this system if they have suitable patients. We conclude the article with a chapter on the relativity of current knowledge, which reflects the turbulent topic of the genetics of Alzheimer's disease, which is constantly changing, expanding and updating, and may bring answers to a number of currently unanswered questions.

• MeSH
• Alzheimer Disease * diagnosis   genetics   classification   MeSH
• Amyloid beta-Protein Precursor analysis   genetics   MeSH
• Apolipoproteins E analysis   genetics   classification   MeSH
• Epigenesis, Genetic genetics   MeSH
• Genetic Background MeSH
• Genetic Testing * methods   MeSH
• Humans MeSH
• Presenilins analysis   genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH
• Geographicals
• Slovakia MeSH

AIM: Astrocytes respond to stressors by acquiring a reactive state characterized by changes in their morphology and function. Molecules underlying reactive astrogliosis, however, remain largely unknown. Given that several studies observed increase in the Amyloid Precursor Protein (APP) in reactive astrocytes, we here test whether APP plays a role in reactive astrogliosis. METHODS: We investigated whether APP instigates reactive astroglios by examining in vitro and in vivo the morphology and function of naive and APP-deficient astrocytes in response to APP and well-established stressors. RESULTS: Overexpression of APP in cultured astrocytes led to remodeling of the intermediate filament network, enhancement of cytokine production, and activation of cellular programs centered around the interferon (IFN) pathway, all signs of reactive astrogliosis. Conversely, APP deletion abrogated remodeling of the intermediate filament network and blunted expression of IFN-stimulated gene products in response to lipopolysaccharide. Following traumatic brain injury (TBI), mouse reactive astrocytes also exhibited an association between APP and IFN, while APP deletion curbed the increase in glial fibrillary acidic protein observed canonically in astrocytes in response to TBI. CONCLUSIONS: The APP thus represents a candidate molecular inducer and regulator of reactive astrogliosis. This finding has implications for understanding pathophysiology of neurodegenerative and other diseases of the nervous system characterized by reactive astrogliosis and opens potential new therapeutic avenues targeting APP and its pathways to modulate reactive astrogliosis.

• MeSH
• Amyloid beta-Protein Precursor * metabolism   genetics   MeSH
• Astrocytes * metabolism   pathology   MeSH
• Gliosis * metabolism   pathology   MeSH
• Cells, Cultured MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Brain Injuries, Traumatic metabolism   pathology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Experimental studies in flies, mice, and humans suggest a significant role of impaired axonal transport in the pathogenesis of Alzheimer's disease (AD). The mechanisms underlying these impairments in axonal transport, however, remain poorly understood. Here we report that the Swedish familial AD mutation causes a standstill of the amyloid precursor protein (APP) in the axons at the expense of its reduced anterograde transport. The standstill reflects the perturbed directionality of the axonal transport of APP, which spends significantly more time traveling in the retrograde direction. This ineffective movement is accompanied by an enhanced association of dynactin-1 with APP, which suggests that reduced anterograde transport of APP is the result of enhanced activation of the retrograde molecular motor dynein by dynactin-1. The impact of the Swedish mutation on axonal transport is not limited to the APP vesicles since it also reverses the directionality of a subset of early endosomes, which become enlarged and aberrantly accumulate in distal locations. In addition, it also reduces the trafficking of lysosomes due to their less effective retrograde movement. Altogether, our experiments suggest a pivotal involvement of retrograde molecular motors and transport in the mechanisms underlying impaired axonal transport in AD and reveal significantly more widespread derangement of axonal transport pathways in the pathogenesis of AD.

• MeSH
• Alzheimer Disease * metabolism   genetics   pathology   MeSH
• Amyloid beta-Protein Precursor * genetics   metabolism   MeSH
• Axonal Transport * genetics   MeSH
• Axons metabolism   pathology   MeSH
• Dynactin Complex metabolism   genetics   MeSH
• Dyneins metabolism   MeSH
• Endosomes metabolism   genetics   MeSH
• Genetic Variation MeSH
• Humans MeSH
• Lysosomes metabolism   MeSH
• Mutation MeSH
• Mice MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The aberrantly expressed microRNAs (miRNAs) including miR-29c-3p have been reported in the brains of Alzheimer's disease (AD) patients in recent researches. Nevertheless, the functional role and underlying molecular mechanism of miR-29c-3p in AD pathogenesis are still not well elucidated. The purpose of this study was to examine whether miR-29c-3p regulated beta-Ameyloid (Abeta)-induced neurotoxicity by targeting beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1). The expressions of miR 29c 3p and BACE1 mRNA and protein levels in Abeta-treated PC12 cellular AD model were examined by qRT-PCR and western blot analyses. Luciferase reporter assay verified the potential target of miR 29c 3p. Cell viability, apoptosis, and caspase-3 activity in PC12 cells were detected by the MTT assay, flow cytometry, and caspase-3 activity assay, respectively. Our results indicated that miR-29c-3p downregulation and BACE1 upregulation existed in the cellular AD model of PC12 cells. Moreover, miR-29c-3p directly inhibited BACE1 expression. miR-29c-3p overexpression and BACE1 knockdown strengthened Abeta-induced cell apoptosis, and caspase-3 activity in PC12 cells, which was partially eliminated by over-expression of BACE1. Conversely, BACE1 knockdown reversed the miR-29c-3p inhibition- mediated inhibitory effect on Abeta-induced cell toxicity, apoptosis, and caspase-3 activity in PC12 cells. Considering, miR-29c-3p attenuated Abeta-induced neurotoxicity through targeting BACE1 in an cellular AD model of PC12, providing a potential therapeutic target for AD treatment.

• MeSH
• Alzheimer Disease * metabolism   MeSH
• Amyloid beta-Peptides toxicity   genetics   metabolism   MeSH
• Amyloid beta-Protein Precursor genetics   metabolism   MeSH
• Aspartic Acid Endopeptidases genetics   metabolism   MeSH
• Caspase 3 metabolism   MeSH
• Rats MeSH
• Humans MeSH
• MicroRNAs * genetics   metabolism   MeSH
• Cell Line, Tumor MeSH
• Amyloid Precursor Protein Secretases genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

The exact signaling leading to neurological dysfunction in neurodegenerative diseases is currently unknown. We hypothesize that the c-Jun N-terminal kinase (JNK) signaling pathway is a potential therapeutic target for neurodegenerative diseases. This postulate rests on extensive data from cell and animal experimental studies, demonstrating that JNK signaling plays a crucial role in the pathogenesis of neurodegenerative diseases. The sustained activation of JNK leads to synaptic dysfunction and even neuronal apoptosis, ultimately resulting in memory deficits and neurodegeneration. JNK phosphorylates the amyloid precursor protein and tau, ultimately resulting in the formation of extraneuronal senile plaques and intraneuronal neurofibrillary tangles. Our hypothesis could be validated by investigating the cerebral cortex of elderly chimpanzees injected with phosphorylated JNK or transgenic pig and chimpanzee models established using gene editing technology including CRISPR. This hypothesis provides clues for further understanding the molecular mechanisms of neurodegenerative diseases and the development of potential target therapeutic drugs.

• MeSH
• Alzheimer Disease genetics   MeSH
• Amyloid beta-Peptides * metabolism   MeSH
• Amyloid beta-Protein Precursor * genetics   metabolism   MeSH
• Phosphorylation MeSH
• Gene Targeting * MeSH
• JNK Mitogen-Activated Protein Kinases metabolism   MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Cerebral Cortex metabolism   pathology   MeSH
• Neurodegenerative Diseases pathology   MeSH
• Neurons metabolism   MeSH
• Pan troglodytes MeSH
• Swine MeSH
• tau Proteins metabolism   MeSH
• Signal Transduction * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

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
• Alzheimer Disease * metabolism   MeSH
• Amyloid beta-Peptides metabolism   MeSH
• Plaque, Amyloid pathology   MeSH
• Amyloid beta-Protein Precursor genetics   metabolism   MeSH
• Diabetes Mellitus, Type 2 * MeSH
• Prolactin-Releasing Hormone metabolism   pharmacology   MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Cerebellum MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Presenilin-1 genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH