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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 -
Brain : a Journal of Neurology Feb 2023Alzheimer's disease is the most common neurodegenerative disease, characterized by dementia and premature death. Early-onset familial Alzheimer's disease is caused in...
Alzheimer's disease is the most common neurodegenerative disease, characterized by dementia and premature death. Early-onset familial Alzheimer's disease is caused in part by pathogenic variants in presenilin 1 (PSEN1) and presenilin 2 (PSEN2), and alternative splicing of these two genes has been implicated in both familial and sporadic Alzheimer's disease. Here, we leveraged targeted isoform-sequencing to characterize thousands of complete PSEN1 and PSEN2 transcripts in the prefrontal cortex of individuals with sporadic Alzheimer's disease, familial Alzheimer's disease (carrying PSEN1 and PSEN2 variants), and controls. Our results reveal alternative splicing patterns of PSEN2 specific to sporadic Alzheimer's disease, including a human-specific cryptic exon present in intron 9 of PSEN2 as well as a 77 bp intron retention product before exon 6 that are both significantly elevated in sporadic Alzheimer's disease samples, alongside a significantly lower percentage of canonical full-length PSEN2 transcripts versus familial Alzheimer's disease samples and controls. Both alternatively spliced products are predicted to generate a prematurely truncated PSEN2 protein and were corroborated in an independent cerebellum RNA-sequencing dataset. In addition, our data in PSEN variant carriers is consistent with the hypothesis that PSEN1 and PSEN2 variants need to produce full-length but variant proteins to contribute to the onset of Alzheimer's disease, although intriguingly there were far fewer full-length transcripts carrying pathogenic alleles versus wild-type alleles in PSEN2 variant carriers. Finally, we identify frequent RNA editing at Alu elements present in an extended 3' untranslated region in PSEN2. Overall, this work expands the understanding of PSEN1 and PSEN2 variants in Alzheimer's disease, shows that transcript differences in PSEN2 may play a role in sporadic Alzheimer's disease, and suggests novel mechanisms of Alzheimer's disease pathogenesis.
Topics: Humans; Alzheimer Disease; Amyloid beta-Protein Precursor; Mutation; Presenilin-2; Presenilin-1; Neurodegenerative Diseases
PubMed: 35949106
DOI: 10.1093/brain/awac294 -
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 -
Current Protein & Peptide Science 2020Alzheimer's disease (AD) is a progressive brain disorder and one of the most common causes of dementia and death. AD can be of two types; early-onset and late-onset,... (Review)
Review
Alzheimer's disease (AD) is a progressive brain disorder and one of the most common causes of dementia and death. AD can be of two types; early-onset and late-onset, where late-onset AD occurs sporadically while early-onset AD results from a mutation in any of the three genes that include amyloid precursor protein (APP), presenilin 1 (PSEN 1) and presenilin 2 (PSEN 2). Biologically, AD is defined by the presence of the distinct neuropathological profile that consists of the extracellular β-amyloid (Aβ) deposition in the form of diffuse neuritic plaques, intraneuronal neurofibrillary tangles (NFTs) and neuropil threads; in dystrophic neuritis, consisting of aggregated hyperphosphorylated tau protein. Elevated levels of (Aβ), total tau (t-tau) and phosphorylated tau (ptau) in cerebrospinal fluid (CSF) have become an important biomarker for the identification of this neurodegenerative disease. The aggregation of Aβ peptide derived from amyloid precursor protein initiates a series of events that involve inflammation, tau hyperphosphorylation and its deposition, in addition to synaptic dysfunction and neurodegeneration, ultimately resulting in dementia. The current review focuses on the role of proteomes in the pathogenesis of AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Biomarkers; Brain; Dementia; Gene Expression Regulation; Humans; Mutation; Neurofibrillary Tangles; Phosphorylation; Presenilin-1; Presenilin-2; Protein Aggregates; Proteome; tau Proteins
PubMed: 32957903
DOI: 10.2174/1389203721666200921152246 -
International Journal of Molecular... Mar 2020Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive dysfunction and behavioral impairment. In China, the number of AD patients... (Review)
Review
Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive dysfunction and behavioral impairment. In China, the number of AD patients is growing rapidly, which poses a considerable burden on society and families. In recent years, through the advancement of genome-wide association studies, second-generation gene sequencing technology, and their application in AD genetic research, more genetic loci associated with the risk for AD have been discovered, including , and , which provides new ideas for the etiology and treatment of AD. This review summarizes three early-onset AD causative genes (, , and ) and some late-onset AD susceptibility genes and their mutation sites newly discovered in China, and briefly introduces the potential mechanisms of these genetic susceptibilities in the pathogenesis of AD, which would help in understanding the genetic mechanisms underlying this devastating disease.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Asian People; China; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Mutation; Presenilin-1; Presenilin-2
PubMed: 32235595
DOI: 10.3390/ijms21072381 -
Annals of the New York Academy of... Dec 2019The endoplasmic reticulum (ER) and mitochondria are fundamental organelles highly interconnected with a specialized set of proteins in cells. ER-mitochondrial... (Review)
Review
The endoplasmic reticulum (ER) and mitochondria are fundamental organelles highly interconnected with a specialized set of proteins in cells. ER-mitochondrial interconnections form specific microdomains, called mitochondria-associated ER membranes, that have been found to play important roles in calcium signaling and lipid homeostasis, and more recently in mitochondrial dynamics, inflammation, and autophagy. It is not surprising that perturbations in ER-mitochondria connections can result in the progression of disease, especially neurological disorders; hence, their architecture and regulation are crucial in determining the fate of cells and disease. The molecular identity of the specialized proteins regulating ER-mitochondrial crosstalk remains unclear. Our discussion here describes the physical and functional crosstalk between these two dynamic organelles and emphasizes the outcome of altered ER-mitochondrial interconnections in neurological disorders.
Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Animals; Autophagy; Brain Ischemia; Calcium; Calcium Signaling; Cell Line, Tumor; Disease Progression; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; GTP Phosphohydrolases; Homeostasis; Humans; Huntington Disease; Inflammation; Lipids; Mice; Mitochondria; Mitochondrial Dynamics; Mitochondrial Membrane Transport Proteins; Mitochondrial Membranes; Nervous System Diseases; Parkinson Disease; Presenilins; Rats; Vesicular Transport Proteins
PubMed: 31460675
DOI: 10.1111/nyas.14212 -
CNS Neuroscience & Therapeutics Feb 2024Alzheimer's disease (AD) is a significant global health concern, and it is crucial that we find effective methods to prevent or slow down AD progression. Recent studies...
AIMS
Alzheimer's disease (AD) is a significant global health concern, and it is crucial that we find effective methods to prevent or slow down AD progression. Recent studies have highlighted the essential role of blood vessels in clearing Aβ, a protein that contributes to AD. Scientists are exploring blood biomarkers as a potential tool for future AD diagnosis. One promising method that may help prevent AD is remote ischemic conditioning (RIC). RIC involves using sub-lethal ischemic-reperfusion cycles on limbs. However, a comprehensive understanding of how RIC can prevent AD and its long-term effectiveness is still lacking. Further research is essential to fully comprehend the potential benefits of RIC in preventing AD.
METHODS
Female wild-type (WT) and APP/PS1 transgenic rats, aged 12 months, underwent ovariectomy and were subsequently assigned to WT, APP/PS1, and APP/PS1 + RIC groups. RIC was conducted five times a week for 4 weeks. The rats' depressive and cognitive behaviors were evaluated using force swimming, open-field tests, novel objective recognition, elevated plus maze, and Barnes maze tests. Evaluation of the neurovascular unit (NVU), synapses, vasculature, astrocytes, and microglia was conducted using immunofluorescence staining (IF), Western blot (WB), and transmission electron microscopy (TEM). Additionally, the cerebro-vasculature was examined using micro-CT, and cerebral blood flow (CBF) was measured using Speckle Doppler. Blood-brain barrier (BBB) permeability was determined by measuring the Evans blue leakage. Finally, Aβ levels in the rat frontal cortex were measured using WB, ELISA, or IF staining.
RESULTS
RIC enhanced memory-related protein expression and rescued depressive-like behavior and cognitive decline in APP/PS1 transgenic rats. Additionally, the intervention protected NVU in the rat frontal cortex, as evidenced by (1) increased expression of TJ (tight junction) proteins, pericyte marker PDGFRβ, and glucose transporter 1 (GLUT1), as well as decreased VCAM1; (2) mitigation of ultrastructure impairment in neuron, cerebral vascular, and astrocyte; (3) upregulation of A2 astrocyte phenotype markers and downregulation of A1 phenotype markers, indicating a shift toward a healthier phenotype. Correspondingly, RIC intervention alleviated neuroinflammation, as evidenced by the decreased Iba1 level, a microglia marker. Meanwhile, RIC intervention elevated CBF in frontal cortex of the rats. Notably, RIC intervention effectively suppressed Aβ toxicity, as demonstrated by the enhancement of α-secretase and attenuation of β-secretase (BACE1) and γ- secretase and Aβ1-42 and Aβ1-40 levels as well.
CONCLUSION
Chronic RIC intervention exerts vascular and neuroprotective roles, suggesting that RIC could be a promising therapeutic strategy targeting the BBB and NVU during AD development.
Topics: Mice; Rats; Female; Animals; Blood-Brain Barrier; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Mice, Transgenic; Rats, Transgenic; Aspartic Acid Endopeptidases; Alzheimer Disease; Cognitive Dysfunction; Disease Models, Animal; Presenilin-1
PubMed: 38379185
DOI: 10.1111/cns.14613 -
Journal of Neuroinflammation Jan 2024Widescale evidence points to the involvement of glia and immune pathways in the progression of Alzheimer's disease (AD). AD-associated iPSC-derived glial cells show a...
BACKGROUND
Widescale evidence points to the involvement of glia and immune pathways in the progression of Alzheimer's disease (AD). AD-associated iPSC-derived glial cells show a diverse range of AD-related phenotypic states encompassing cytokine/chemokine release, phagocytosis and morphological profiles, but to date studies are limited to cells derived from PSEN1, APOE and APP mutations or sporadic patients. The aim of the current study was to successfully differentiate iPSC-derived microglia and astrocytes from patients harbouring an AD-causative PSEN2 (N141I) mutation and characterise the inflammatory and morphological profile of these cells.
METHODS
iPSCs from three healthy control individuals and three familial AD patients harbouring a heterozygous PSEN2 (N141I) mutation were used to derive astrocytes and microglia-like cells and cell identity and morphology were characterised through immunofluorescent microscopy. Cellular characterisation involved the stimulation of these cells by LPS and Aβ and analysis of cytokine/chemokine release was conducted through ELISAs and multi-cytokine arrays. The phagocytic capacity of these cells was then indexed by the uptake of fluorescently-labelled fibrillar Aβ.
RESULTS
AD-derived astrocytes and microglia-like cells exhibited an atrophied and less complex morphological appearance than healthy controls. AD-derived astrocytes showed increased basal expression of GFAP, S100β and increased secretion and phagocytosis of Aβ while AD-derived microglia-like cells showed decreased IL-8 secretion compared to healthy controls. Upon immunological challenge AD-derived astrocytes and microglia-like cells showed exaggerated secretion of the pro-inflammatory IL-6, CXCL1, ICAM-1 and IL-8 from astrocytes and IL-18 and MIF from microglia.
CONCLUSION
Our study showed, for the first time, the differentiation and characterisation of iPSC-derived astrocytes and microglia-like cells harbouring a PSEN2 (N141I) mutation. PSEN2 (N141I)-mutant astrocytes and microglia-like cells presented with a 'primed' phenotype characterised by reduced morphological complexity, exaggerated pro-inflammatory cytokine secretion and altered Aβ production and phagocytosis.
Topics: Humans; Astrocytes; Microglia; Induced Pluripotent Stem Cells; Interleukin-8; Alzheimer Disease; Cytokines; Phenotype; Amyloid beta-Peptides; Presenilin-2
PubMed: 38178159
DOI: 10.1186/s12974-023-02951-2 -
EMBO Molecular Medicine Jan 2023Many efforts targeting amyloid-β (Aβ) plaques for the treatment of Alzheimer's Disease thus far have resulted in failures during clinical trials. Regional and temporal...
Many efforts targeting amyloid-β (Aβ) plaques for the treatment of Alzheimer's Disease thus far have resulted in failures during clinical trials. Regional and temporal heterogeneity of efficacy and dependence on plaque maturity may have contributed to these disappointing outcomes. In this study, we mapped the regional and temporal specificity of various anti-Aβ treatments through high-resolution light-sheet imaging of electrophoretically cleared brains. We assessed the effect on amyloid plaque formation and growth in Thy1-APP/PS1 mice subjected to β-secretase inhibitors, polythiophenes, or anti-Aβ antibodies. Each treatment showed unique spatiotemporal Aβ clearance, with polythiophenes emerging as a potent anti-Aβ compound. Furthermore, aligning with a spatial-transcriptomic atlas revealed transcripts that correlate with the efficacy of each Aβ therapy. As observed in this study, there is a striking dependence of specific treatments on the location and maturity of Aβ plaques. This may also contribute to the clinical trial failures of Aβ-therapies, suggesting that combinatorial regimens may be significantly more effective in clearing amyloid deposition.
Topics: Mice; Animals; Microscopy; Mice, Transgenic; Amyloid beta-Peptides; Alzheimer Disease; Brain; Plaque, Amyloid; Disease Models, Animal; Amyloid beta-Protein Precursor; Presenilin-1
PubMed: 36382364
DOI: 10.15252/emmm.202216789 -
Alzheimer's Research & Therapy Aug 2023Studies in animal models of Alzheimer's disease (AD) have provided valuable insights into the molecular and cellular processes underlying neuronal network dysfunction....
BACKGROUND
Studies in animal models of Alzheimer's disease (AD) have provided valuable insights into the molecular and cellular processes underlying neuronal network dysfunction. Whether and how AD-related neurophysiological alterations translate between mice and humans remains however uncertain.
METHODS
We characterized neurophysiological alterations in mice and humans carrying AD mutations in the APP and/or PSEN1 genes, focusing on early pre-symptomatic changes. Longitudinal local field potential recordings were performed in APP/PS1 mice and cross-sectional magnetoencephalography recordings in human APP and/or PSEN1 mutation carriers. All recordings were acquired in the left frontal cortex, parietal cortex, and hippocampus. Spectral power and functional connectivity were analyzed and compared with wildtype control mice and healthy age-matched human subjects.
RESULTS
APP/PS1 mice showed increased absolute power, especially at higher frequencies (beta and gamma) and predominantly between 3 and 6 moa. Relative power showed an overall shift from lower to higher frequencies over almost the entire recording period and across all three brain regions. Human mutation carriers, on the other hand, did not show changes in power except for an increase in relative theta power in the hippocampus. Mouse parietal cortex and hippocampal power spectra showed a characteristic peak at around 8 Hz which was not significantly altered in transgenic mice. Human power spectra showed a characteristic peak at around 9 Hz, the frequency of which was significantly reduced in mutation carriers. Significant alterations in functional connectivity were detected in theta, alpha, beta, and gamma frequency bands, but the exact frequency range and direction of change differed for APP/PS1 mice and human mutation carriers.
CONCLUSIONS
Both mice and humans carrying APP and/or PSEN1 mutations show abnormal neurophysiological activity, but several measures do not translate one-to-one between species. Alterations in absolute and relative power in mice should be interpreted with care and may be due to overexpression of amyloid in combination with the absence of tau pathology and cholinergic degeneration. Future studies should explore whether changes in brain activity in other AD mouse models, for instance, those also including tau pathology, provide better translation to the human AD continuum.
Topics: Animals; Humans; Mice; Alzheimer Disease; Amyloidogenic Proteins; Mice, Transgenic; Mutation; Presenilin-1; Amyloid beta-Protein Precursor
PubMed: 37608393
DOI: 10.1186/s13195-023-01287-6