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Human Gene Therapy Oct 2023Autosomal dominant Alzheimer's disease (ADAD) is a rare early-onset form of Alzheimer's disease, caused by dominant mutations in one of three genes: presenilin 1,...
Autosomal dominant Alzheimer's disease (ADAD) is a rare early-onset form of Alzheimer's disease, caused by dominant mutations in one of three genes: presenilin 1, presenilin 2, and amyloid β precursor protein (APP). Mutations in the presenilin 1 gene () account for the majority of cases, and individuals who inherit a single-mutant allele go on to develop early-onset dementia, ultimately leading to death. The presenilin 1 protein (PS1) is the catalytic subunit of the γ-secretase protease, a tetrameric protease responsible for cleavage of numerous transmembrane proteins, including Notch and the APP. Inclusion of a mutant PS1 subunit in the γ-secretase complex leads to a loss of enzyme function and a preferential reduction of shorter forms of Aβ peptides over longer forms, an established biomarker of ADAD progression in human patients. In this study, we describe the development of a gene therapy vector expressing a wild-type (WT) copy of human to ameliorate the loss of function associated with mutations. We have carried out studies in mouse models using a recombinant AAV9 vector to deliver the gene directly into the central nervous system (CNS) and shown that we can normalize γ-secretase function and slow neurodegeneration in both conditional knockout and mutant knockin models. We have also carried out biodistribution studies in nonhuman primates (NHPs) and demonstrated the ability to achieve broad PS1 protein expression throughout the cortex and the hippocampus, two regions known to be critically involved in ADAD progression. These studies demonstrate preclinical proof of concept that expression of a WT human gene in cells harboring a dominant mutation can correct the γ-secretase dysfunction. In addition, direct administration of the recombinant AAV9 into the NHP brain can achieve broad expression at levels predicted to provide efficacy in the clinic.
Topics: Animals; Mice; Humans; Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Presenilin-1; Tissue Distribution; Amyloid beta-Protein Precursor; Mutation; Genetic Therapy
PubMed: 37578141
DOI: 10.1089/hum.2023.092 -
Signal Transduction and Targeted Therapy Mar 2024Mutations in the Contactin-associated protein-like 2 (CNTNAP2) gene are associated with autism spectrum disorder (ASD), and ectodomain shedding of the CNTNAP2 protein...
Mutations in the Contactin-associated protein-like 2 (CNTNAP2) gene are associated with autism spectrum disorder (ASD), and ectodomain shedding of the CNTNAP2 protein plays a role in its function. However, key enzymes involved in the C-terminal cleavage of CNTNAP2 remain largely unknown, and the effect of ASD-associated mutations on this process and its role in ASD pathogenesis remain elusive. In this report we showed that CNTNAP2 undergoes sequential cleavages by furin, ADAM10/17-dependent α-secretase and presenilin-dependent γ-secretase. We identified that the cleavage sites of ADAM10 and ADAM17 in CNTNAP2 locate at its C-terminal residue I79 and L96, and the main α-cleavage product C79 by ADAM10 is required for the subsequent γ-secretase cleavage to generate CNTNAP2 intracellular domain (CICD). ASD-associated CNTNAP2 mutations impair the α-cleavage to generate C79, and the inhibition leads to ASD-like repetitive and social behavior abnormalities in the Cntnap2 knock-in mice. Finally, exogenous expression of C79 improves autism-like phenotypes in the Cntnap2 knock-in and Cntnap2 knockout mice. This data demonstrates that the α-secretase is essential for CNTNAP2 processing and its function. Our study indicates that inhibition of the cleavage by pathogenic mutations underlies ASD pathogenesis, and upregulation of its C-terminal fragments could have therapeutical potentials for ASD treatment.
Topics: Animals; Mice; Autistic Disorder; Amyloid Precursor Protein Secretases; Autism Spectrum Disorder; Mutation; Mice, Knockout; Contactins; Phenotype; Membrane Proteins; Nerve Tissue Proteins
PubMed: 38424048
DOI: 10.1038/s41392-024-01768-6 -
International Journal of Molecular... Nov 2023Cannabidiol (CBD), a major non-psychoactive component of the cannabis plant, has shown therapeutic potential in Alzheimer's disease (AD). In this study, we identified...
Cannabidiol (CBD), a major non-psychoactive component of the cannabis plant, has shown therapeutic potential in Alzheimer's disease (AD). In this study, we identified potential CBD targets associated with AD using a drug-target binding affinity prediction model and generated CBD analogs using a genetic algorithm combined with a molecular docking system. As a result, we identified six targets associated with AD: Endothelial NOS (ENOS), Myeloperoxidase (MPO), Apolipoprotein E (APOE), Amyloid-beta precursor protein (APP), Disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), and Presenilin-1 (PSEN1). Furthermore, we generated CBD analogs for each target that optimize for all desired drug-likeness properties and physicochemical property filters, resulting in improved pIC50 values and docking scores compared to CBD. Molecular dynamics (MD) simulations were applied to analyze each target's CBD and highest-scoring CBD analogs. The MD simulations revealed that the complexes of ENOS, MPO, and ADAM10 with CBD exhibited high conformational stability, and the APP and PSEN1 complexes with CBD analogs demonstrated even higher conformational stability and lower interaction energy compared to APP and PSEN1 complexes with CBD. These findings demonstrated the capable binding of the six identified targets with CBD and the enhanced binding stability achieved with the developed CBD analogs for each target.
Topics: Humans; Alzheimer Disease; Cannabidiol; Molecular Docking Simulation; Amyloid beta-Protein Precursor; Molecular Dynamics Simulation
PubMed: 37959001
DOI: 10.3390/ijms242116013 -
Alcohol Research : Current Reviews 2024By 2040, 21.6% of Americans will be over age 65, and the population of those older than age 85 is estimated to reach 14.4 million. Although not causative, older age is a... (Review)
Review
PURPOSE
By 2040, 21.6% of Americans will be over age 65, and the population of those older than age 85 is estimated to reach 14.4 million. Although not causative, older age is a risk factor for dementia: every 5 years beyond age 65, the risk doubles; approximately one-third of those older than age 85 are diagnosed with dementia. As current alcohol consumption among older adults is significantly higher compared to previous generations, a pressing question is whether drinking alcohol increases the risk for Alzheimer's disease or other forms of dementia.
SEARCH METHODS
Databases explored included PubMed, Web of Science, and ScienceDirect. To accomplish this narrative review on the effects of alcohol consumption on dementia risk, the literature covered included clinical diagnoses, epidemiology, neuropsychology, postmortem pathology, neuroimaging and other biomarkers, and translational studies. Searches conducted between January 12 and August 1, 2023, included the following terms and combinations: "aging," "alcoholism," "alcohol use disorder (AUD)," "brain," "CNS," "dementia," "Wernicke," "Korsakoff," "Alzheimer," "vascular," "frontotemporal," "Lewy body," "clinical," "diagnosis," "epidemiology," "pathology," "autopsy," "postmortem," "histology," "cognitive," "motor," "neuropsychological," "magnetic resonance," "imaging," "PET," "ligand," "degeneration," "atrophy," "translational," "rodent," "rat," "mouse," "model," "amyloid," "neurofibrillary tangles," "α-synuclein," or "presenilin." When relevant, "species" (i.e., "humans" or "other animals") was selected as an additional filter. Review articles were avoided when possible.
SEARCH RESULTS
The two terms "alcoholism" and "aging" retrieved about 1,350 papers; adding phrases-for example, "postmortem" or "magnetic resonance"-limited the number to fewer than 100 papers. Using the traditional term, "alcoholism" with "dementia" resulted in 876 citations, but using the currently accepted term "alcohol use disorder (AUD)" with "dementia" produced only 87 papers. Similarly, whereas the terms "Alzheimer's" and "alcoholism" yielded 318 results, "Alzheimer's" and "alcohol use disorder (AUD)" returned only 40 citations. As pertinent postmortem pathology papers were published in the 1950s and recent animal models of Alzheimer's disease were created in the early 2000s, articles referenced span the years 1957 to 2024. In total, more than 5,000 articles were considered; about 400 are herein referenced.
DISCUSSION AND CONCLUSIONS
Chronic alcohol misuse accelerates brain aging and contributes to cognitive impairments, including those in the mnemonic domain. The consensus among studies from multiple disciplines, however, is that alcohol misuse can increase the risk for dementia, but not necessarily Alzheimer's disease. Key issues to consider include the reversibility of brain damage following abstinence from chronic alcohol misuse compared to the degenerative and progressive course of Alzheimer's disease, and the characteristic presence of protein inclusions in the brains of people with Alzheimer's disease, which are absent in the brains of those with AUD.
Topics: Humans; Dementia; Alcoholism; Aged; Animals; Aged, 80 and over; Alcohol Drinking; Brain; Alzheimer Disease; Risk Factors
PubMed: 38812709
DOI: 10.35946/arcr.v44.1.03 -
Biomolecules Sep 2023The presenilin-1 (PSEN1) gene is crucial in developing Alzheimer's disease (AD), a progressive neurodegenerative disorder and the most common cause of dementia. Circular...
The presenilin-1 (PSEN1) gene is crucial in developing Alzheimer's disease (AD), a progressive neurodegenerative disorder and the most common cause of dementia. Circular RNAs (circRNAs) are non-coding RNA generated through back-splicing, resulting in a covalently closed circular molecule. This study aimed to investigate PSEN1-gene-derived circular RNAs (circPSEN1s) and their potential functions in AD. Our in silico analysis indicated that circPSEN1s (hsa_circ_0008521 and chr14:73614502-73614802) act as sponge molecules for eight specific microRNAs. Surprisingly, two of these miRNAs (has-mir-4668-5p and has-mir-5584-5p) exclusively interact with circPSEN1s rather than mRNA-PSEN1. Furthermore, the analysis of pathways revealed that these two miRNAs predominantly target mRNAs associated with the PI3K-Akt signaling pathway. With sponging these microRNAs, circPSEN1s were found to protect mRNAs commonly targeted by these miRNAs, including QSER1, BACE2, RNF157, PTMA, and GJD3. Furthermore, the miRNAs sequestered by circPSEN1s have a notable preference for targeting the TGF-β and Hippo signaling pathways. We also demonstrated that circPSEN1s potentially interact with FOXA1, ESR1, HNF1B, BRD4, GATA4, EP300, CBX3, PRDM9, and PPARG proteins. These proteins have a prominent preference for targeting the TGF-β and Notch signaling pathways, where EP300 and FOXA1 have the highest number of protein interactions. Molecular docking analysis also confirms the interaction of these hub proteins and Aβ42 with circPSEN1s. Interestingly, circPSEN1s-targeted molecules (miRNAs and proteins) impacted TGF-β, which served as a shared signaling pathway. Finally, the analysis of microarray data unveiled distinct expression patterns of genes influenced by circPSEN1s (WTIP, TGIF, SMAD4, PPP1CB, and BMPR1A) in the brains of AD patients. In summary, our findings suggested that the interaction of circPSEN1s with microRNAs and proteins could affect the fate of specific mRNAs, interrupt the function of unique proteins, and influence cell signaling pathways, generally TGF-β. Further research is necessary to validate these findings and gain a deeper understanding of the precise mechanisms and significance of circPSEN1s in the context of AD.
Topics: Humans; RNA, Circular; Alzheimer Disease; Presenilin-1; Phosphatidylinositol 3-Kinases; Molecular Docking Simulation; Nuclear Proteins; Transcription Factors; MicroRNAs; RNA, Messenger; Epigenesis, Genetic; Cell Cycle Proteins; Cytoskeletal Proteins; Co-Repressor Proteins
PubMed: 37759801
DOI: 10.3390/biom13091401 -
Neuroscience Letters Nov 2023Alzheimer's disease (AD) is a progressive neurological disorder that affects the central nervous system (CNS), leading to memory and cognitive decline. In AD, the brain... (Review)
Review
Alzheimer's disease (AD) is a progressive neurological disorder that affects the central nervous system (CNS), leading to memory and cognitive decline. In AD, the brain experiences three main structural changes: a significant decrease in the quantity of neurons, the development of neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein, and the formation of amyloid beta (Aβ) or senile plaques, which are protein deposits found outside cells and surrounded by dystrophic neurites. Genetic studies have identified four genes associated with autosomal dominant or familial early-onset AD (FAD): amyloid precursor protein (APP), presenilin 1 (PS1), presenilin 2 (PS2), and apolipoprotein E (ApoE). The formation of plaques primarily involves the accumulation of Aβ, which can be influenced by mutations in APP, PS1, PS2, or ApoE genes. Mutations in the APP and presenilin (PS) proteins can cause an increased amyloid β peptides production, especially the further form of amyloidogenic known as Aβ42. Apart from genetic factors, environmental factors such as cytokines and neurotoxins may also have a significant impact on the development and progression of AD by influencing the formation of amyloid plaques and intracellular tangles. Exploring the causes and implications of protein aggregation in the brain could lead to innovative therapeutic approaches. Some promising therapy strategies that have reached the clinical stage include using acetylcholinesterase inhibitors, estrogen, nonsteroidal anti-inflammatory drugs (NSAIDs), antioxidants, and antiapoptotic agents. The most hopeful therapeutic strategies involve inhibiting activity of secretase and preventing the β-amyloid oligomers and fibrils formation, which are associated with the β-amyloid fibrils accumulation in AD. Additionally, immunotherapy development holds promise as a progressive therapeutic approach for treatment of AD. Recently, the two primary categories of brain stimulation techniques that have been studied for the treatment of AD are invasive brain stimulation (IBS) and non-invasive brain stimulation (NIBS). In this article, the amyloid proteins that play a significant role in the AD formation, the mechanism of disease formation as well as new drugs utilized to treat of AD will be reviewed.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Acetylcholinesterase; Amyloid beta-Protein Precursor; Presenilin-1; Apolipoproteins E
PubMed: 37866702
DOI: 10.1016/j.neulet.2023.137532 -
Neural Regeneration Research Apr 2024Alzheimer's disease is a progressive neurodegenerative disorder and the most common cause of dementia that principally affects older adults. Pathogenic factors, such as... (Review)
Review
Alzheimer's disease is a progressive neurodegenerative disorder and the most common cause of dementia that principally affects older adults. Pathogenic factors, such as oxidative stress, an increase in acetylcholinesterase activity, mitochondrial dysfunction, genotoxicity, and neuroinflammation are present in this syndrome, which leads to neurodegeneration. Neurodegenerative pathologies such as Alzheimer's disease are considered late-onset diseases caused by the complex combination of genetic, epigenetic, and environmental factors. There are two main types of Alzheimer's disease, known as familial Alzheimer's disease (onset < 65 years) and late-onset or sporadic Alzheimer's disease (onset ≥ 65 years). Patients with familial Alzheimer's disease inherit the disease due to rare mutations on the amyloid precursor protein (APP), presenilin 1 and 2 (PSEN1 and PSEN2) genes in an autosomal-dominantly fashion with closely 100% penetrance. In contrast, a different picture seems to emerge for sporadic Alzheimer's disease, which exhibits numerous non-Mendelian anomalies suggesting an epigenetic component in its etiology. Importantly, the fundamental pathophysiological mechanisms driving Alzheimer's disease are interfaced with epigenetic dysregulation. However, the dynamic nature of epigenetics seems to open up new avenues and hope in regenerative neurogenesis to improve brain repair in Alzheimer's disease or following injury or stroke in humans. In recent years, there has been an increase in interest in using natural products for the treatment of neurodegenerative illnesses such as Alzheimer's disease. Through epigenetic mechanisms, such as DNA methylation, non-coding RNAs, histone modification, and chromatin conformation regulation, natural compounds appear to exert neuroprotective effects. While we do not purport to cover every in this work, we do attempt to illustrate how various phytochemical compounds regulate the epigenetic effects of a few Alzheimer's disease-related genes.
PubMed: 37843220
DOI: 10.4103/1673-5374.382232 -
Neural Regeneration Research Aug 2023We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations... (Review)
Review
We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors. Specifically, we discussed randomized clinical trials in subjects with Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis bearing pathogenic gene mutations, and glucocerebrosidase-associated Parkinson's disease. Learning potential lessons to improve future therapeutic approaches is the aim of this review. Two long-term, controlled trials on three anti-β-amyloid monoclonal antibodies (solanezumab, gantenerumab and crenezumab) in subjects carrying Alzheimer's disease-linked mutated genes encoding for amyloid precursor protein or presenilin 1 or presenilin 2 failed to show cognitive or functional benefits. A major trial on tominersen, an antisense oligonucleotide designed to reduce the production of the huntingtin protein in subjects with Huntington's disease, was prematurely interrupted because the drug failed to show higher efficacy than placebo and, at highest doses, led to worsened outcomes. A 28-week trial of tofersen, an antisense oligonucleotide for superoxide dismutase 1 in patients with amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations failed to show significant beneficial effects but the 1-year open label extension of this study indicated better clinical and functional outcomes in the group with early tofersen therapy. A trial of venglustat, a potent and brain-penetrant glucosylceramide synthase inhibitor, in Parkinson's disease subjects with heterozygous glucocerebrosidase gene mutations revealed worsened clinical and cognitive performance of patients on the enzyme inhibitor compared to placebo. We concluded that clinical trials in neurodegenerative diseases with a genetic basis should test monoclonal antibodies, antisense oligonucleotides or gene editing directed against the mutated enzyme or the mutated substrate without dramatically affecting physiological wild-type variants.
PubMed: 36751779
DOI: 10.4103/1673-5374.363185 -
Journal of Neuroinflammation Nov 2023Cyanidin-3-O-glucoside (C3G) is a natural anthocyanin with antioxidant, anti-inflammatory, and antitumor properties. However, as the effects of C3G on the amyloidogenic...
Cyanidin-3-O-glucoside (C3G) is a natural anthocyanin with antioxidant, anti-inflammatory, and antitumor properties. However, as the effects of C3G on the amyloidogenic pathway, autophagy, tau phosphorylation, neuronal cell death, and synaptic plasticity in Alzheimer's disease models have not been reported, we attempted to investigate the same in the brains of APPswe/PS1ΔE9 mice were analyzed. After oral administration of C3G (30 mg/kg/day) for 16 weeks, the cortical and hippocampal regions in the brains of APPswe/PS1ΔE9 mice were analyzed. C3G treatment reduced the levels of soluble and insoluble Aβ (Aβ40 and Aβ42) peptides and reduced the protein expression of the amyloid precursor protein, presenilin-1, and β-secretase in the cortical and hippocampal regions. And C3G treatment upregulated the expression of autophagy-related markers, LC3B-II, LAMP-1, TFEB, and PPAR-α and downregulated that of SQSTM1/p62, improving the autophagy of Aβ plaques and neurofibrillary tangles. In addition, C3G increased the protein expression of phosphorylated-AMPK/AMPK and Sirtuin 1 and decreased that of mitogen-activated protein kinases, such as phosphorylated-Akt/Akt and phosphorylated-ERK/ERK, thus demonstrating its neuroprotective effects. Furthermore, C3G regulated the PI3K/Akt/GSK3β signaling by upregulating phosphorylated-Akt/Akt and phosphorylated-GSK3β/GSK3β expression. C3G administration mitigated tau phosphorylation and improved synaptic function and plasticity by upregulating the expression of synapse-associated proteins synaptophysin and postsynaptic density protein-95. Although the potential of C3G in the APPswe/PS1ΔE9 mouse models has not yet been reported, oral administration of the C3G is shown to protect the brain and improve cognitive behavior.
Topics: Mice; Animals; Mice, Transgenic; Anthocyanins; Glycogen Synthase Kinase 3 beta; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; AMP-Activated Protein Kinases; Alzheimer Disease; Cognition; Brain; Glucosides; Amyloid beta-Peptides
PubMed: 37978414
DOI: 10.1186/s12974-023-02950-3 -
Stem Cell Reports Jul 2023Alzheimer's disease (AD) is the most common neurodegenerative disorder, but its root cause may lie in neurodevelopment. PSEN1 mutations cause the majority of familial...
Alzheimer's disease (AD) is the most common neurodegenerative disorder, but its root cause may lie in neurodevelopment. PSEN1 mutations cause the majority of familial AD, potentially by disrupting proper Notch signaling, causing early unnoticed cellular changes that affect later AD progression. While rodent models are useful for modeling later stages of AD, human induced pluripotent stem cell-derived cortical spheroids (hCSs) allow access to studying the human cortex at the cellular level over the course of development. Here, we show that the PSEN1 L435F heterozygous mutation affects hCS development, increasing size, increasing progenitors, and decreasing post-mitotic neurons as a result of increased Notch target gene expression during early hCS development. We also show altered Aβ expression and neuronal activity at later hCS stages. These results contrast previous findings, showing how individual PSEN1 mutations may differentially affect neurodevelopment and may give insight into fAD progression to provide earlier time points for more effective treatments.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Induced Pluripotent Stem Cells; Mutation; Neurons; Presenilin-1
PubMed: 37352850
DOI: 10.1016/j.stemcr.2023.05.018