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Neuron Oct 2023Presenilin mutations that alter γ-secretase activity cause familial Alzheimer's disease (AD), whereas ApoE4, an apolipoprotein for cholesterol transport, predisposes to...
Presenilin mutations that alter γ-secretase activity cause familial Alzheimer's disease (AD), whereas ApoE4, an apolipoprotein for cholesterol transport, predisposes to sporadic AD. Both sporadic and familial AD feature synaptic dysfunction. Whether γ-secretase is involved in cholesterol metabolism and whether such involvement impacts synaptic function remains unknown. Here, we show that in human neurons, chronic pharmacological or genetic suppression of γ-secretase increases synapse numbers but decreases synaptic transmission by lowering the presynaptic release probability without altering dendritic or axonal arborizations. In search of a mechanism underlying these synaptic impairments, we discovered that chronic γ-secretase suppression robustly decreases cholesterol levels in neurons but not in glia, which in turn stimulates neuron-specific cholesterol-synthesis gene expression. Suppression of cholesterol levels by HMG-CoA reductase inhibitors (statins) impaired synaptic function similar to γ-secretase inhibition. Thus, γ-secretase enables synaptic function by maintaining cholesterol levels, whereas the chronic suppression of γ-secretase impairs synapses by lowering cholesterol levels.
Topics: Humans; Alzheimer Disease; Amyloid Precursor Protein Secretases; Lipid Metabolism; Neurons; Cholesterol; Presenilin-1; Amyloid beta-Peptides
PubMed: 37543038
DOI: 10.1016/j.neuron.2023.07.005 -
Ageing Research Reviews Nov 2023Alzheimer's disease (AD) represents the most frequent type of dementia in elderly people. Two major forms of the disease exist: sporadic - the causes of which have not... (Review)
Review
Alzheimer's disease (AD) represents the most frequent type of dementia in elderly people. Two major forms of the disease exist: sporadic - the causes of which have not yet been fully understood - and familial - inherited within families from generation to generation, with a clear autosomal dominant transmission of mutations in Presenilin 1 (PSEN1), 2 (PSEN2) or Amyloid Precursors Protein (APP) genes. The main hallmark of AD consists of extracellular deposits of amyloid-beta (Aβ) peptide and intracellular deposits of the hyperphosphorylated form of the tau protein. An ever-growing body of research supports the viral infectious hypothesis of sporadic forms of AD. In particular, it has been shown that several herpes viruses (i.e., HHV-1, HHV-2, HHV-3 or varicella zoster virus, HHV-4 or Epstein Barr virus, HHV-5 or cytomegalovirus, HHV-6A and B, HHV-7), flaviviruses (i.e., Zika virus, Dengue fever virus, Japanese encephalitis virus) as well as Human Immunodeficiency Virus (HIV), hepatitis viruses (HAV, HBV, HCV, HDV, HEV), SARS-CoV2, Ljungan virus (LV), Influenza A virus and Borna disease virus, could increase the risk of AD. Here, we summarized and discussed these results. Based on these findings, significant issues for future studies are also put forward.
Topics: Animals; Humans; Aged; Alzheimer Disease; Epstein-Barr Virus Infections; RNA, Viral; Herpesvirus 4, Human; Amyloid beta-Protein Precursor; Amyloid beta-Peptides; Virus Diseases; Zika Virus; Zika Virus Infection
PubMed: 37704050
DOI: 10.1016/j.arr.2023.102068 -
Molecular Neurodegeneration Dec 2023Regulatory T cells (Tregs) maintain immune tolerance. While Treg-mediated neuroprotective activities are now well-accepted, the lack of defined antigen specificity...
BACKGROUND
Regulatory T cells (Tregs) maintain immune tolerance. While Treg-mediated neuroprotective activities are now well-accepted, the lack of defined antigen specificity limits their therapeutic potential. This is notable for neurodegenerative diseases where cell access to injured brain regions is required for disease-specific therapeutic targeting and improved outcomes. To address this need, amyloid-beta (Aβ) antigen specificity was conferred to Treg responses by engineering the T cell receptor (TCR) specific for Aβ (TCR). The TCR were developed from disease-specific T cell effector (Teff) clones. The ability of Tregs expressing a transgenic TCR (TCR -Tregs) to reduce Aβ burden, transform effector to regulatory cells, and reverse disease-associated neurotoxicity proved beneficial in an animal model of Alzheimer's disease.
METHODS
TCR -Tregs were generated by CRISPR-Cas9 knockout of endogenous TCR and consequent incorporation of the transgenic TCR identified from Aβ reactive Teff monoclones. Antigen specificity was confirmed by MHC-Aβ-tetramer staining. Adoptive transfer of TCR-Tregs to mice expressing a chimeric mouse-human amyloid precursor protein and a mutant human presenilin-1 followed measured behavior, immune, and immunohistochemical outcomes.
RESULTS
TCR-Tregs expressed an Aβ-specific TCR. Adoptive transfer of TCR-Tregs led to sustained immune suppression, reduced microglial reaction, and amyloid loads. F-fluorodeoxyglucose radiolabeled TCR-Treg homed to the brain facilitating antigen specificity. Reduction in amyloid load was associated with improved cognitive functions.
CONCLUSIONS
TCR-Tregs reduced amyloid burden, restored brain homeostasis, and improved learning and memory, supporting the increased therapeutic benefit of antigen specific Treg immunotherapy for AD.
Topics: Animals; Humans; Mice; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloidogenic Proteins; Disease Models, Animal; Mice, Transgenic; Presenilin-1; Receptors, Antigen, T-Cell; T-Lymphocytes, Regulatory
PubMed: 38111016
DOI: 10.1186/s13024-023-00692-7 -
Molecular Cell Nov 2023γ-Secretases mediate the regulated intramembrane proteolysis (RIP) of more than 150 integral membrane proteins. We developed an unbiased γ-secretase substrate...
γ-Secretases mediate the regulated intramembrane proteolysis (RIP) of more than 150 integral membrane proteins. We developed an unbiased γ-secretase substrate identification (G-SECSI) method to study to what extent these proteins are processed in parallel. We demonstrate here parallel processing of at least 85 membrane proteins in human microglia in steady-state cell culture conditions. Pharmacological inhibition of γ-secretase caused substantial changes of human microglial transcriptomes, including the expression of genes related to the disease-associated microglia (DAM) response described in Alzheimer disease (AD). While the overall effects of γ-secretase deficiency on transcriptomic cell states remained limited in control conditions, exposure of mouse microglia to AD-inducing amyloid plaques strongly blocked their capacity to mount this putatively protective DAM cell state. We conclude that γ-secretase serves as a critical signaling hub integrating the effects of multiple extracellular stimuli into the overall transcriptome of the cell.
Topics: Mice; Animals; Humans; Amyloid Precursor Protein Secretases; Proteome; Signal Transduction; Membrane Proteins; Alzheimer Disease
PubMed: 37977120
DOI: 10.1016/j.molcel.2023.10.029 -
Neuron Jun 2024Highly penetrant autosomal dominant Alzheimer's disease (ADAD) comprises a distinct disease entity as compared to the far more prevalent form of AD in which common...
Highly penetrant autosomal dominant Alzheimer's disease (ADAD) comprises a distinct disease entity as compared to the far more prevalent form of AD in which common variants collectively contribute to risk. The downstream pathways that distinguish these AD forms in specific cell types have not been deeply explored. We compared single-nucleus transcriptomes among a set of 27 cases divided among PSEN1-E280A ADAD carriers, sporadic AD, and controls. Autophagy genes and chaperones clearly defined the PSEN1-E280A cases compared to sporadic AD. Spatial transcriptomics validated the activation of chaperone-mediated autophagy genes in PSEN1-E280A. The PSEN1-E280A case in which much of the brain was spared neurofibrillary pathology and harbored a homozygous APOE3-Christchurch variant revealed possible explanations for protection from AD pathology including overexpression of LRP1 in astrocytes, increased expression of FKBP1B, and decreased PSEN1 expression in neurons. The unique cellular responses in ADAD and sporadic AD require consideration when designing clinical trials.
Topics: Alzheimer Disease; Humans; Presenilin-1; Male; Female; Low Density Lipoprotein Receptor-Related Protein-1; Sequence Analysis, RNA; Autophagy; Transcriptome; Aged; Neurons; Middle Aged; Astrocytes; Brain; Tacrolimus Binding Proteins; Aged, 80 and over; Single-Cell Analysis
PubMed: 38417436
DOI: 10.1016/j.neuron.2024.02.009 -
Alzheimer's & Dementia : the Journal of... Nov 2023One goal of the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment.... (Review)
Review
INTRODUCTION
One goal of the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants.
METHODS
LEADS amyloid-positive early-onset Alzheimer's disease (EOAD) or negative early-onset non-AD (EOnonAD) cases were whole exome sequenced (N = 299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar-age cognitively normal controls in the Parkinson's Progression Markers Initiative (PPMI) study.
RESULTS
Previously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases.
DISCUSSION
Results suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases.
HIGHLIGHTS
Sequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a key resource for early-onset Alzheimer's genetic research.
Topics: Humans; Alzheimer Disease; Amyloid beta-Protein Precursor; C9orf72 Protein; Genetic Testing; Longitudinal Studies; Mutation; Presenilin-1; Presenilin-2
PubMed: 37801072
DOI: 10.1002/alz.13482 -
Cell Reports Feb 2024Mutations that cause familial Alzheimer's disease (FAD) are found in amyloid precursor protein (APP) and presenilin, the catalytic component of γ-secretase, that...
Mutations that cause familial Alzheimer's disease (FAD) are found in amyloid precursor protein (APP) and presenilin, the catalytic component of γ-secretase, that together produce amyloid β-peptide (Aβ). Nevertheless, whether Aβ is the primary disease driver remains controversial. We report here that FAD mutations disrupt initial proteolytic events in the multistep processing of APP substrate C99 by γ-secretase. Cryoelectron microscopy reveals that a substrate mimetic traps γ-secretase during the transition state, and this structure aligns with activated enzyme-substrate complex captured by molecular dynamics simulations. In silico simulations and in cellulo fluorescence microscopy support stabilization of enzyme-substrate complexes by FAD mutations. Neuronal expression of C99 and/or presenilin-1 in Caenorhabditis elegans leads to synaptic loss only with FAD-mutant transgenes. Designed mutations that stabilize the enzyme-substrate complex and block Aβ production likewise led to synaptic loss. Collectively, these findings implicate the stalled process-not the products-of γ-secretase cleavage of substrates in FAD pathogenesis.
Topics: Animals; Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Cryoelectron Microscopy; Mutation; Caenorhabditis elegans; Molecular Dynamics Simulation
PubMed: 38349793
DOI: 10.1016/j.celrep.2024.113761 -
Ageing Research Reviews Nov 2023Alzheimer's disease (AD) is a progressive neurodegenerative disease, characterized by memory loss and multiple cognitive impairments. Genetic mutations cause a small... (Review)
Review
Alzheimer's disease (AD) is a progressive neurodegenerative disease, characterized by memory loss and multiple cognitive impairments. Genetic mutations cause a small proportion (1-2%) of early-onset AD, with mutations in amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2). Major contributing factors of late-onset AD are ApoE4 genotype, traumatic brain injury, diabetes, obesity, hypertension, cardiovascular conditions, in addition to lifestyle factors, such as unhealthy diet and lack of physical exercise. Disease progression can be delayed and/or prevented to a greater extent by adopting healthy lifestyle with balanced and antioxidant enriched diet and daily exercise. The interaction and interplay of diet, exercise, age, and pharmacological interventions holds a crucial role in the progression, pathogenesis and management of AD and its comorbidities, including diabetes, obesity, hypertension and cardiovascular conditions. Antioxidant enriched diet contributes to brain health, glucose control, weight management, and cardiovascular well-being. Regular exercise removes toxins including free radicals and enhances insulin sensitivity, and supports cardiovascular function. In the current article, we discussed, the role of diet, and exercise in aging, AD and other conditions including diabetes, obesity, hypertension, cardiovascular conditions. This article also highlights the impact of medication, socioeconomic and lifestyle factors, and pharmacological interventions. These aspects were discussed in different races and ethnic groups in Texas, and the US.
Topics: Humans; Animals; Mice; Alzheimer Disease; Antioxidants; Neurodegenerative Diseases; Amyloid beta-Protein Precursor; Exercise; Aging; Chronic Disease; Obesity; Diet; Diabetes Mellitus; Hypertension; Amyloid beta-Peptides; Disease Models, Animal; Mice, Transgenic
PubMed: 37832608
DOI: 10.1016/j.arr.2023.102091 -
Frontiers in Neuroscience 2023This review uncovers the intricate relationship between presenilins, calcium, and mitochondria in the context of Alzheimer's disease (AD), with a particular focus on the... (Review)
Review
This review uncovers the intricate relationship between presenilins, calcium, and mitochondria in the context of Alzheimer's disease (AD), with a particular focus on the involvement of presenilin mutations in mitochondrial dysfunction. So far, it is unclear whether the impairment of mitochondrial function arises primarily from damage inflicted by -amyloid upon mitochondria or from the disruption of calcium homeostasis due to presenilins dysfunctions. The roles of presenilins in mitophagy, autophagy, mitochondrial dynamics, and many other functions, non--secretase related, also require close attention in future research. Resolution of contradictions in understanding of presenilins cellular functions are needed for new effective therapeutic strategies for AD.
PubMed: 37575294
DOI: 10.3389/fnins.2023.1249815