-
EMBO Molecular Medicine Jun 2016Despite continuing debate about the amyloid β-protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an... (Review)
Review
Despite continuing debate about the amyloid β-protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ-secretase has provided a linchpin: all dominant mutations causing early-onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild-type APP gene in Down's syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients' brains can decrease synapse number, inhibit long-term potentiation, and enhance long-term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD-relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau-positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid-PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Humans; Mice, Transgenic; Presenilins; Rats
PubMed: 27025652
DOI: 10.15252/emmm.201606210 -
Frontiers in Bioscience (Elite Edition) Jan 2013Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder. A majority of cases manifest as a late onset sporadic form but genetically the disease... (Review)
Review
Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder. A majority of cases manifest as a late onset sporadic form but genetically the disease is divided into familial cases and sporadic cases. The familial form is due to mutations in three major genes (amyloid precursor protein (APP) gene, presenilin1 (PSEN1) gene and presenilin 2 (PSEN2) gene). In contrast, many genetic and environmental factors may contribute to determining the sporadic AD form. Despite many years of research and great progress in the knowledge of the molecular pathogenesis of AD, a full understanding of the etiology of the sporadic form is still not yet in reach. Genome-wide association studies (GWASs) revealed the genetic complexity of the disease and recent studies suggested that epigenetic mechanisms may play an essential role in disease development. This review provides an overview of all the milestones in AD genetic research, as well as the new and promising approach, in order to better understand the genetic profile for predicting the risk of AD.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Apolipoproteins E; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Models, Genetic; Mutation; Neurofibrillary Tangles; Presenilins
PubMed: 23276979
DOI: 10.2741/e605 -
Science Translational Medicine Apr 2011Alzheimer's disease (AD) was first described a little more than 100 years ago. It is the most common cause of dementia with an estimated prevalence of 30 million people... (Review)
Review
Alzheimer's disease (AD) was first described a little more than 100 years ago. It is the most common cause of dementia with an estimated prevalence of 30 million people worldwide, a number that is expected to quadruple in 40 years. There currently is no effective treatment that delays the onset or slows the progression of AD. However, major scientific advances in the areas of genetics, biochemistry, cell biology, and neuroscience over the past 25 years have changed the way we think about AD. This review discusses some of the challenges to translating these basic molecular and cellular discoveries into clinical therapies. Current information suggests that if the disease is detected before the onset of overt symptoms, it is possible that treatments based on knowledge of underlying pathogenesis can and will be effective.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Disease Progression; Humans; Presenilins; tau Proteins
PubMed: 21471435
DOI: 10.1126/scitranslmed.3002369 -
The Journal of Neuroscience : the... Dec 2022Kainate receptors (KARs) form a family of ionotropic glutamate receptors that regulate the activity of neuronal networks by both presynaptic and postsynaptic mechanisms....
Kainate receptors (KARs) form a family of ionotropic glutamate receptors that regulate the activity of neuronal networks by both presynaptic and postsynaptic mechanisms. Their implication in pathologies is well documented for epilepsy. The higher prevalence of epileptic symptoms in Alzheimer's disease (AD) patients questions the role of KARs in AD. Here we investigated whether the synaptic expression and function of KARs was impaired in mouse models of AD. We addressed this question by immunostaining and electrophysiology at synapses between mossy fibers and CA3 pyramidal cells, in which KARs are abundant and play a prominent physiological role. We observed a decrease of the immunostaining for GluK2 in the stratum lucidum in CA3, and of the amplitude and decay time of synaptic currents mediated by GluK2-containing KARs in an amyloid mouse model (APP/PS1) of AD. Interestingly, a similar phenotype was observed in CA3 pyramidal cells in male and female mice with a genetic deletion of either presenilin or APP/APLP2 as well as in organotypic cultures treated with γ-secretase inhibitors. Finally, the GluK2 protein interacts with full-length and C-terminal fragments of APP. Overall, our data suggest that APP stabilizes KARs at synapses, possibly through a transsynaptic mechanism, and this interaction is under the control the γ-secretase proteolytic activity of presenilin. Synaptic impairment correlates strongly with cognitive deficits in Alzheimer's disease (AD). In this context, many studies have addressed the dysregulation of AMPA and NMDA ionotropic glutamate receptors. Kainate receptors (KARs), which form the third family of iGluRs, represent an underestimated actor in the regulation of neuronal circuits and have not yet been examined in the context of AD. Here we provide evidence that synaptic KARs are markedly impaired in a mouse model of AD. Additional experiments indicate that the γ-secretase activity of presenilin acting on the amyloid precursor protein controls synaptic expression of KAR. This study clearly indicates that KARs should be taken into consideration whenever addressing synaptic dysfunction and related cognitive deficits in the context of AD.
Topics: Animals; Female; Male; Mice; Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Kainic Acid; Mossy Fibers, Hippocampal; Presenilin-1; Presenilins; Receptors, Kainic Acid; Synapses; GluK2 Kainate Receptor
PubMed: 36288945
DOI: 10.1523/JNEUROSCI.0297-22.2022 -
Biochimica Et Biophysica Acta Dec 2013Presenilin is the catalytic component of the γ-secretase complex, a membrane-embedded aspartyl protease that plays a central role in biology and in the pathogenesis of... (Review)
Review
Presenilin is the catalytic component of the γ-secretase complex, a membrane-embedded aspartyl protease that plays a central role in biology and in the pathogenesis of Alzheimer's disease. Upon assembly with its three protein cofactors (nicastrin, Aph-1 and Pen-2), presenilin undergoes autoproteolysis into two subunits, each of which contributes one of the catalytic aspartates to the active site. A family of presenilin homologs, including signal peptide peptidase, possess proteolytic activity without the need for other protein factors, and these simpler intramembrane aspartyl proteases have given insight into the action of presenilin within the γ-secretase complex. Cellular and molecular studies support a nine-transmembrane topology for presenilins and their homologs, and small-molecule inhibitors and cysteine scanning with crosslinking have suggested certain presenilin residues and regions that contribute to substrate recognition and handling. Identification of partial complexes has also offered clues to protein-protein interactions within the γ-secretase complex. Biophysical methods have allowed 3D views of the γ-secretase complex and presenilins. Most recently, the crystal structure of a microbial presenilin homolog has confirmed a nine-transmembrane topology and intramembranous location and proximity of the two conserved and essential aspartates. The crystal structure also provides a platform for the formulation of specific hypotheses regarding substrate interaction and catalysis as well as the pathogenic mechanism of Alzheimer-causing presenilin mutations. This article is part of a Special Issue entitled: Intramembrane Proteases.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Coenzymes; Crystallography, X-Ray; Endopeptidases; Humans; Membrane Glycoproteins; Membrane Proteins; Models, Molecular; Peptide Hydrolases; Presenilin-1; Presenilin-2; Protein Binding; Protein Structure, Tertiary; Proteolysis; Signal Transduction; Substrate Specificity
PubMed: 24099007
DOI: 10.1016/j.bbamem.2013.04.015 -
Genome Biology Oct 2002The presenilins are evolutionarily conserved transmembrane proteins that regulate cleavage of certain other proteins in their transmembrane domains. The clinical... (Review)
Review
The presenilins are evolutionarily conserved transmembrane proteins that regulate cleavage of certain other proteins in their transmembrane domains. The clinical significance of this regulation is shown by the contribution of presenilin mutations to 20-50% of early-onset cases of inherited Alzheimer's disease. Although the precise molecular mechanism underlying presenilin function or dysfunction remains elusive, presenilins are thought to be part of a complex of proteins that has 'gamma-secretase cleavage' activity, which is clearly central in the pathogenesis of Alzheimer's disease. Mutations in presenilins increase the production of the longer isoforms of amyloid beta peptide, which are neurotoxic and prone to self-aggregation. Biochemical studies indicate that the presenilins do not act alone but operate within large heteromeric protein complexes, whose components and enzymatic core are the subject of much study and controversy; one essential component is nicastrin. The presenilin primary sequence is remarkably well conserved in eukaryotes, suggesting some functional conservation; indeed, defects caused by mutations in the nemotode presenilin homolog can be rescued by human presenilin.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Protein Precursor; Animals; Aspartic Acid Endopeptidases; Endopeptidases; Evolution, Molecular; Humans; Membrane Proteins; Mutation; Organ Specificity; Presenilin-1; Presenilin-2
PubMed: 12429067
DOI: 10.1186/gb-2002-3-11-reviews3014 -
Neuro-degenerative Diseases 2014The presenilin(PS) genes harbor approximately 90% of the identified mutations linked to familial forms of Alzheimer's disease, and the presenilin (PS) proteins are... (Review)
Review
The presenilin(PS) genes harbor approximately 90% of the identified mutations linked to familial forms of Alzheimer's disease, and the presenilin (PS) proteins are essential components of the γ-secretase complex involved in the proteolytic cleavage of type I receptors, such as Notch and the amyloid precursor protein. Genetic analysis employing cell type-specific conditional knockout technology highlighted the importance of PS in the adult brain, including learning and memory, synaptic function and age-dependent neuronal survival. In the central synapse, PS regulates neurotransmitter release, short- and long-term synaptic plasticity and calcium homeostasis. However, the molecular mechanisms by which PS maintains these essential functions are less clear. Although many γ-secretase substrates have been identified, their physiological relevance is often unclear. The findings that nicastrin and PS conditional knockout mice exhibit similar deficits in memory and age-dependent neurodegeneration are consistent with the notion that γ-secretase-dependent activities of PS are required for the maintenance of memory and neuronal survival, though the γ-secretase physiological substrates, Notch receptors, are not targets of PS in the adult brain. Thus, despite of the intense interest in PS since its identification in 1995, more work is needed to define the molecular and cellular mechanisms by which PS controls brain functions and the dysfunction conferred by disease-causing mutations.
Topics: Alzheimer Disease; Animals; Humans; Presenilins
PubMed: 24107444
DOI: 10.1159/000354971 -
Journal of Alzheimer's Disease : JAD 2011The Alzheimer's disease (AD)-associated amyloid-β protein precursor (AβPP) is cleaved by α-, β-, and presenilin (PS)/γ-secretases through sequential regulated... (Review)
Review
The Alzheimer's disease (AD)-associated amyloid-β protein precursor (AβPP) is cleaved by α-, β-, and presenilin (PS)/γ-secretases through sequential regulated proteolysis. These proteolytic events control the generation of the pathogenic amyloid-β (Aβ) peptide, which excessively accumulates in the brains of individuals afflicted by AD. A growing number of additional proteins cleaved by PS/γ-secretase continue to be discovered. Similarly to AβPP, most of these proteins are type-I transmembrane proteins involved in vital signaling functions regulating cell fate, adhesion, migration, neurite outgrowth, or synaptogenesis. All the identified proteins share common structural features, which are typical for their proteolysis. The consequences of the PS/γ-secretase-mediated cleavage on the function of many of these proteins are largely unknown. Here, we review the current literature on the proteolytic processing mediated by the versatile PS/γ-secretase complex. We begin by discussing the steps of AβPP processing and PS/γ-secretase complex composition and localization, which give clues to how and where the processing of other PS/γ-secretase substrates may take place. Then we summarize the typical features of PS/γ-secretase-mediated protein processing. Finally, we recapitulate the current knowledge on the possible physiological function of PS/γ-secretase-mediated cleavage of specific substrate proteins.
Topics: Amyloid Precursor Protein Secretases; Animals; Humans; Presenilins; Substrate Specificity
PubMed: 21335653
DOI: 10.3233/JAD-2011-101065 -
Cells Mar 2019The presenilin (PS) proteins exert a crucial role in the pathogenesis of Alzheimer disease (AD) by mediating the intramembranous cleavage of amyloid precursor protein... (Review)
Review
The presenilin (PS) proteins exert a crucial role in the pathogenesis of Alzheimer disease (AD) by mediating the intramembranous cleavage of amyloid precursor protein (APP) and the generation of amyloid β-protein (Aβ). The two homologous proteins PS1 and PS2 represent the catalytic subunits of distinct γ-secretase complexes that mediate a variety of cellular processes, including membrane protein metabolism, signal transduction, and cell differentiation. While the intramembrane cleavage of select proteins by γ-secretase is critical in the regulation of intracellular signaling pathways, the plethora of identified protein substrates could also indicate an important role of these enzyme complexes in membrane protein homeostasis. In line with this notion, PS proteins and/or γ-secretase has also been implicated in autophagy, a fundamental process for the maintenance of cellular functions and homeostasis. Dysfunction in the clearance of proteins in the lysosome and during autophagy has been shown to contribute to neurodegeneration. This review summarizes the recent knowledge about the role of PS proteins and γ-secretase in membrane protein metabolism and trafficking, and the functional relation to lysosomal activity and autophagy.
Topics: Amyloid Precursor Protein Secretases; Animals; Autophagy; Cell Membrane; Humans; Membrane Proteins; Presenilins; Proteostasis
PubMed: 30823664
DOI: 10.3390/cells8030209 -
Aging Cell Jun 2007When properly controlled, Ca2+ fluxes across the plasma membrane and between intracellular compartments play critical roles in fundamental functions of neurons,... (Review)
Review
When properly controlled, Ca2+ fluxes across the plasma membrane and between intracellular compartments play critical roles in fundamental functions of neurons, including the regulation of neurite outgrowth and synaptogenesis, synaptic transmission and plasticity, and cell survival. During aging, and particularly in neurodegenerative disorders, cellular Ca2+-regulating systems are compromised resulting in synaptic dysfunction, impaired plasticity and neuronal degeneration. Oxidative stress, perturbed energy metabolism and aggregation of disease-related proteins (amyloid beta-peptide, alpha-synuclein, huntingtin, etc.) adversely affect Ca2+ homeostasis by mechanisms that have been elucidated recently. Alterations of Ca2+-regulating proteins in the plasma membrane (ligand- and voltage-gated Ca2+ channels, ion-motive ATPases, and glucose and glutamate transporters), endoplasmic reticulum (presenilin-1, Herp, and ryanodine and inositol triphosphate receptors), and mitochondria (electron transport chain proteins, Bcl-2 family members, and uncoupling proteins) are implicated in age-related neuronal dysfunction and disease. The adverse effects of aging on neuronal Ca2+ regulation are subject to modification by genetic (mutations in presenilins, alpha-synuclein, huntingtin, or Cu/Zn-superoxide dismutase; apolipoprotein E isotype, etc.) and environmental (dietary energy intake, exercise, exposure to toxins, etc.) factors that may cause or affect the risk of neurodegenerative disease. A better understanding of the cellular and molecular mechanisms that promote or prevent disturbances in cellular Ca2+ homeostasis during aging may lead to novel approaches for therapeutic intervention in neurological disorders such as Alzheimer's and Parkinson's diseases and stroke.
Topics: Amyloid; Animals; Apoptosis; Calcium; Calcium Signaling; Endoplasmic Reticulum; Humans; Microscopy, Fluorescence; Models, Biological; Nerve Degeneration; Neurodegenerative Diseases; Oxidative Stress; Parkinson Disease; Presenilins
PubMed: 17328689
DOI: 10.1111/j.1474-9726.2007.00275.x