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Frontiers in Molecular Neuroscience 2024Alzheimer's disease (AD) is a complex neurodegenerative disorder and the most common form of dementia. There are two main types of AD: familial and sporadic. Familial AD... (Review)
Review
Alzheimer's disease (AD) is a complex neurodegenerative disorder and the most common form of dementia. There are two main types of AD: familial and sporadic. Familial AD is linked to mutations in amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2). On the other hand, sporadic AD is the more common form of the disease and has genetic, epigenetic, and environmental components that influence disease onset and progression. Investigating the epigenetic mechanisms associated with AD is essential for increasing understanding of pathology and identifying biomarkers for diagnosis and treatment. Chemical covalent modifications on DNA and RNA can epigenetically regulate gene expression at transcriptional and post-transcriptional levels and play protective or pathological roles in AD and other neurodegenerative diseases.
PubMed: 38726308
DOI: 10.3389/fnmol.2024.1398026 -
Proceedings of the National Academy of... Oct 2023Mutations in the ( and ) genes are the major cause of early-onset familial Alzheimer's disease (FAD). Presenilin (PS) is the catalytic subunit of the γ-secretase...
Mutations in the ( and ) genes are the major cause of early-onset familial Alzheimer's disease (FAD). Presenilin (PS) is the catalytic subunit of the γ-secretase complex, which cleaves type I transmembrane proteins, such as Notch and the amyloid precursor protein (APP), and plays an evolutionarily conserved role in the protection of neuronal survival during aging. FAD mutations exhibit impaired γ-secretase activity in cell culture, in vitro, and knockin (KI) mouse brains, and the L435F mutation is the most severe in reducing γ-secretase activity and is located closest to the active site of γ-secretase. Here, we report that introduction of the codon-optimized wild-type human cDNA by adeno-associated virus 9 (AAV9) results in broadly distributed, sustained, low to moderate levels of human PS1 (hPS1) expression and rescues impaired γ-secretase activity in the cerebral cortex of mutant mice either lacking PS or expressing the L435F KI allele, as evaluated by endogenous γ-secretase substrates of APP and recombinant γ-secretase products of Notch intracellular domain and Aβ peptides. Furthermore, introduction of hPS1 by AAV9 alleviates impairments of synaptic plasticity and learning and memory in mutant mice. Importantly, AAV9 delivery of hPS1 ameliorates neurodegeneration in the cerebral cortex of aged mutant mice, as shown by the reversal of age-dependent loss of cortical neurons and elevated microgliosis and astrogliosis. These results together show that moderate hPS1 expression by AAV9 is sufficient to rescue impaired γ-secretase activity, synaptic and memory deficits, and neurodegeneration caused by mutations in mouse models.
Topics: Humans; Mice; Animals; Aged; Amyloid Precursor Protein Secretases; Presenilin-1; Alzheimer Disease; Amyloid beta-Protein Precursor; Mutation; Memory Disorders; Presenilin-2; Amyloid beta-Peptides
PubMed: 37816062
DOI: 10.1073/pnas.2306714120 -
Nature Communications Aug 2023Autosomal dominant Alzheimer's disease (ADAD) is genetically determined, but variability in age of symptom onset suggests additional factors may influence cognitive...
Autosomal dominant Alzheimer's disease (ADAD) is genetically determined, but variability in age of symptom onset suggests additional factors may influence cognitive trajectories. Although apolipoprotein E (APOE) genotype and educational attainment both influence dementia onset in sporadic AD, evidence for these effects in ADAD is limited. To investigate the effects of APOE and educational attainment on age-related cognitive trajectories in ADAD, we analyzed data from 675 Presenilin-1 E280A mutation carriers and 594 non-carriers. Here we show that age-related cognitive decline is accelerated in ADAD mutation carriers who also have an APOE e4 allele compared to those who do not and delayed in mutation carriers who also have an APOE e2 allele compared to those who do not. Educational attainment is protective and moderates the effect of APOE on cognition. Despite ADAD mutation carriers being genetically determined to develop dementia, age-related cognitive decline may be influenced by other genetic and environmental factors.
Topics: Humans; Alzheimer Disease; Apolipoproteins; Apolipoproteins E; Cognition; Educational Status; Genotype
PubMed: 37612284
DOI: 10.1038/s41467-023-40775-z -
Alzheimer's & Dementia : the Journal of... Mar 2024Early-life stress (ES) increases the risk for Alzheimer's disease (AD). We and others have shown that ES aggravates amyloid-beta (Aβ) pathology and promotes cognitive...
INTRODUCTION
Early-life stress (ES) increases the risk for Alzheimer's disease (AD). We and others have shown that ES aggravates amyloid-beta (Aβ) pathology and promotes cognitive dysfunction in APP/PS1 mice, but underlying mechanisms remain unclear.
METHODS
We studied how ES affects the hippocampal synaptic proteome in wild-type (WT) and APP/PS1 mice at early and late pathological stages, and validated hits using electron microscopy and immunofluorescence.
RESULTS
The hippocampal synaptosomes of both ES-exposed WT and early-stage APP/PS1 mice showed a relative decrease in actin dynamics-related proteins and a relative increase in mitochondrial proteins. ES had minimal effects on older WT mice, while strongly affecting the synaptic proteome of advanced stage APP/PS1 mice, particularly the expression of astrocytic and mitochondrial proteins.
DISCUSSION
Our data show that ES and amyloidosis share pathogenic pathways involving synaptic mitochondrial dysfunction and lipid metabolism, which may underlie the observed impact of ES on the trajectory of AD.
Topics: Mice; Animals; Lipid Metabolism; Mice, Transgenic; Proteome; Adverse Childhood Experiences; Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Mitochondria; Mitochondrial Proteins; Disease Models, Animal; Amyloid beta-Protein Precursor; Presenilin-1
PubMed: 38055782
DOI: 10.1002/alz.13569 -
Aging and Disease Apr 2024Alzheimer's disease (AD) and Alzheimer's disease-related disorders (ADRD) are progressive neurodegenerative diseases without cure. Alzheimer's disease occurs in 2 forms,... (Review)
Review
Alzheimer's disease (AD) and Alzheimer's disease-related disorders (ADRD) are progressive neurodegenerative diseases without cure. Alzheimer's disease occurs in 2 forms, early-onset familial AD and late-onset sporadic AD. Early-onset AD is a rare (~1%), autosomal dominant, caused by mutations in presenilin-1, presenilin-2, and amyloid precursor protein genes and the other is a late-onset, prevalent and is evolved due to age-associated complex interactions between environmental and genetic factors, in addition to apolipoprotein E4 polymorphism. Cellular senescence, promoting the impairment of physical and mental functions is constituted to be the main cause of aging, the primary risk factor for AD, which results in progressive loss of cognitive function, memory, and visual-spatial skills for an individual to live or act independently. Despite significant progress in the understanding of the biology and pathophysiology of AD, we continue to lack definitive early detectable biomarkers and/or drug targets that can be used to delay the development of AD and ADRD in elderly populations. However, recent developments in the studies of DNA double-strand breaks result in the release of fragmented DNA into the bloodstream and contribute to higher levels of cell-free DNA (cf-DNA). This fragmented cf-DNA can be released into the bloodstream from various cell types, including normal cells and cells undergoing apoptosis or necrosis and elevated levels of cf-DNA in the blood have the potential to serve as blood blood-based biomarker for early detection of AD and ADRD. The overall goal of our study is to discuss the latest developments in circulating cell-free DNA into the blood in the progression of AD and ADRD. Our article summarized the status of research on double-strand breaks and circulating cell-free DNA in both healthy and disease states and how these recent developments can be used to develop early detectable biomarkers for AD and ADRD. Our article also discussed the impact of lifestyle and epigenetic factors that are involved in DNA double-strand breaks and circulating cell-free DNA in AD and ADRD.
PubMed: 38607732
DOI: 10.14336/AD.2024.0329 -
Advanced Science (Weinheim,... Nov 2023A hallmark of Alzheimer's disease (AD) is the senile plaque, which contains β-amyloid peptides (Aβ). Ganglioside GM1 is the most common brain ganglioside. However, the...
A hallmark of Alzheimer's disease (AD) is the senile plaque, which contains β-amyloid peptides (Aβ). Ganglioside GM1 is the most common brain ganglioside. However, the mechanism of GM1 in modulating Aβ processing is rarely known. Aβ levels are detected by using Immunohistochemistry (IHC) and enzyme-linked immune-sorbent assay (ELISA). Cryo-electron microscopy (Cryo-EM) is used to determine the structure of γ-secretase supplemented with GM1. The levels of the cleavage of amyloid precursor protein (APP)/Cadherin/Notch1 are detected using Western blot analysis. Y maze, object translocation, and Barnes maze are performed to evaluate cognitive functions. GM1 leads to conformational change of γ-secretase structure and specifically accelerates γ-secretase cleavage of APP without affecting other substrates including Notch1, potentially through its interaction with the N-terminal fragment of presenilin 1 (PS1). Reduction of GM1 levels decreases amyloid plaque deposition and improves cognitive dysfunction. This study reveals the mechanism of GM1 in Aβ generation and provides the evidence that decreasing GM1 levels represents a potential strategy in AD treatment. These results provide insights into the detailed mechanism of the effect of GM1 on PS1, representing a step toward the characterization of its novel role in the modulation of γ-secretase activity and the pathogenesis of AD.
Topics: Humans; Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; G(M1) Ganglioside; Cryoelectron Microscopy
PubMed: 37759382
DOI: 10.1002/advs.202303411 -
Glia Jan 2024Alzheimer's disease (AD) is among the most prevalent age-related neurodegenerative diseases. Endothelial cell (EC) senescence was discovered in the AD brain, but its...
Alzheimer's disease (AD) is among the most prevalent age-related neurodegenerative diseases. Endothelial cell (EC) senescence was discovered in the AD brain, but its function in AD pathogenesis was unidentified. Here we created an AD mouse model with EC senescence (APP/PS1;TERF2DN mice) by intercrossing APP/PS1 mice with Tie2 promoter-driven dominant negative telomeric repeat-binding factor 2 transgenic mice (TERF2DN-Tg mice). We evaluated cognitive functions and AD brain pathology in APP/PS1;TERF2DN mice. Surprisingly, compared with the control APP/PS1 mice, APP/PS1;TERF2DN mice demonstrated the attenuation of cognitive impairment and amyloid-β (Aβ) pathology, accompanied by the compaction of Aβ plaques with increased microglial coverage and reduced neurite dystrophy. Moreover, we evaluated whether EC senescence could affect microglial morphology and phagocytosis of Aβ. Compared with wild-type mice, microglia in TERF2DN-Tg mice display increased numbers of endpoints (a morphometric parameter to quantify the number of processes) and Aβ phagocytosis and related gene expression. Single-cell RNA-sequencing analysis showed that compared with APP/PS1 mouse microglia, APP/PS1;TERF2DN mouse microglia displayed a modest decline in disease-associated microglia, accompanied by an altered direction of biological process branching from antigen synthesis and arrangement to ribonucleoprotein complex biogenesis. Our outcomes indicate that EC senescence alters microglia toward a protective phenotype with a rise in phagocytic and barrier roles, and may offer a clue to create a novel preventive/therapeutic method to treat AD.
Topics: Mice; Animals; Alzheimer Disease; Amyloid beta-Protein Precursor; Presenilin-1; Mice, Inbred C57BL; Amyloid beta-Peptides; Mice, Transgenic; Cognitive Dysfunction; Microglia; Plaque, Amyloid; Disease Models, Animal
PubMed: 37610154
DOI: 10.1002/glia.24461 -
International Journal of Oncology Nov 2023T cell acute lymphoblastic leukemia (T‑ALL), a neoplasm derived from T cell lineage‑committed lymphoblasts, is characterized by genetic alterations that result in...
T cell acute lymphoblastic leukemia (T‑ALL), a neoplasm derived from T cell lineage‑committed lymphoblasts, is characterized by genetic alterations that result in activation of oncogenic transcription factors and the NOTCH1 pathway activation. The NOTCH is a transmembrane receptor protein activated by γ‑secretase. γ‑secretase inhibitors (GSIs) are a NOTCH‑targeted therapy for T‑ALL. However, their clinical application has not been successful due to adverse events (primarily gastrointestinal toxicity), limited efficacy, and drug resistance caused by several mechanisms, including activation of the AKT/mTOR pathway. Nelfinavir is an human immunodeficiency virus 1 aspartic protease inhibitor and has been repurposed as an anticancer drug. It acts by inducing endoplasmic reticulum (ER) stress and inhibiting the AKT/mTOR pathway. Thus, it was hypothesized that nelfinavir might inhibit the NOTCH pathway via γ‑secretase inhibition and blockade of aspartic protease presenilin, which would make nelfinavir effective against NOTCH‑associated T‑ALL. The present study assessed the efficacy of nelfinavir against T‑ALL cells and investigated mechanisms of action and in preclinical treatment studies using a transgenic mouse model. Nelfinavir blocks presenilin 1 processing and inhibits γ‑secretase activity as well as the NOTCH1 pathway, thus suppressing T‑ALL cell viability. Additionally, microarray analysis of nelfinavir‑treated T‑ALL cells showed that nelfinavir upregulated mRNA levels of (glutathione‑specific γ‑glutamylcyclotransferase 1, a negative regulator of NOTCH) and sestrin 2 (; a negative regulator of mTOR). As both factors are upregulated by ER stress, this confirmed that nelfinavir induced ER stress in T‑ALL cells. Moreover, nelfinavir suppressed mRNA expression in microarray analyses. These findings suggest that nelfinavir inhibited the NOTCH1 pathway by downregulating mRNA expression, upregulating and suppressing γ‑secretase via presenilin 1 inhibition and the mTOR pathway by upregulating via ER stress induction. Further, nelfinavir exhibited therapeutic efficacy against T‑ALL in an transgenic mouse model. Collectively, these findings highlight the potential of nelfinavir as a novel therapeutic candidate for treatment of patients with T‑ALL.
Topics: Humans; Mice; Animals; Nelfinavir; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Presenilin-1; Proto-Oncogene Proteins c-akt; Amyloid Precursor Protein Secretases; TOR Serine-Threonine Kinases; Enzyme Inhibitors; Transcription Factors; Mice, Transgenic; RNA, Messenger; Receptor, Notch1; Cell Line, Tumor; Sestrins
PubMed: 37800623
DOI: 10.3892/ijo.2023.5576 -
Gut Apr 2024Mutations in presenilin genes are the major cause of Alzheimer's disease. However, little is known about their expression and function in the gut. In this study, we...
OBJECTIVE
Mutations in presenilin genes are the major cause of Alzheimer's disease. However, little is known about their expression and function in the gut. In this study, we identify the presenilins Psen1 and Psen2 as key molecules that maintain intestinal homoeostasis.
DESIGN
Human inflammatory bowel disease (IBD) and control samples were analysed for Psen1 expression. Newly generated intestinal epithelium-specific Psen1-deficient, Psen2-deficient and inducible Psen1/Psen2 double-deficient mice were used to dissect the functional role of presenilins in intestinal homoeostasis.
RESULTS
Psen1 expression was regulated in experimental gut inflammation and in patients with IBD. Induced deletion of Psen1 and Psen2 in mice caused rapid weight loss and spontaneous development of intestinal inflammation. Mice exhibited epithelial barrier disruption with bacterial translocation and deregulation of key pathways for nutrient uptake. Wasting disease was independent of gut inflammation and dysbiosis, as depletion of microbiota rescued Psen-deficient animals from spontaneous colitis development but not from weight loss. On a molecular level, intestinal epithelial cells lacking Psen showed impaired Notch signalling and dysregulated epithelial differentiation.
CONCLUSION
Overall, our study provides evidence that Psen1 and Psen2 are important guardians of intestinal homoeostasis and future targets for barrier-promoting therapeutic strategies in IBD.
PubMed: 38684238
DOI: 10.1136/gutjnl-2023-331622 -
The Journal of Comparative Neurology Aug 2023Pathological changes in the medial prefrontal cortex (mPFC) and astrocytes are closely associated with Alzheimer's disease (AD). Voluntary running has been found to...
Pathological changes in the medial prefrontal cortex (mPFC) and astrocytes are closely associated with Alzheimer's disease (AD). Voluntary running has been found to effectively delay AD. However, the effects of voluntary running on mPFC astrocytes in AD are unclear. A total of 40 10-month-old male amyloid precursor protein/presenilin 1 (APP/PS1) mice and 40 wild-type (WT) mice were randomly divided into control and running groups, and the running groups underwent voluntary running for 3 months. Mouse cognition was assessed by the novel object recognition (NOR), Morris water maze (MWM), and Y maze tests. The effects of voluntary running on mPFC astrocytes were investigated using immunohistochemistry, immunofluorescence, western blotting, and stereology. APP/PS1 mice performed significantly worse than WT mice in the NOR, MWM, and Y maze tests, and voluntary running improved the performance of APP/PS1 mice in these tests. The total number of mPFC astrocytes was increased, cell bodies were enlarged, and protrusion number and length were increased in AD mice compared with WT mice, but there was no difference in component 3 (C3) levels in the mPFC (total mPFC level); however, C3 and S100B levels in astrocytes were increased in AD mice. Voluntary running reduced the total number of astrocytes and S100B levels in astrocytes and increased the density of PSD95 puncta in direct contact with astrocyte protrusions in the APP/PS1 mouse mPFC. Three months of voluntary running inhibited astrocyte hyperplasia and S100B expression in astrocytes, increased the density of synapses in contact with astrocytes, and improved cognitive function in APP/PS1 mice.
Topics: Male; Animals; Mice; Mice, Transgenic; Cognition; Running; Astrocytes; Prefrontal Cortex; Synapses; Disease Models, Animal; Alzheimer Disease; Physical Conditioning, Animal
PubMed: 37146123
DOI: 10.1002/cne.25485