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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 -
Biomolecules Mar 2023Old age increases the risk of Alzheimer's disease (AD), the most common neurodegenerative disease, a devastating disorder of the human mind and the leading cause of... (Review)
Review
Old age increases the risk of Alzheimer's disease (AD), the most common neurodegenerative disease, a devastating disorder of the human mind and the leading cause of dementia. Worldwide, 50 million people have the disease, and it is estimated that there will be 150 million by 2050. Today, healthcare for AD patients consumes 1% of the global economy. According to the amyloid cascade hypothesis, AD begins in the brain by accumulating and aggregating Aβ peptides and forming β-amyloid fibrils (Aβ42). However, in clinical trials, reducing Aβ peptide production and amyloid formation in the brain did not slow cognitive decline or improve daily life in AD patients. Prevention studies in cognitively unimpaired people at high risk or genetically destined to develop AD also have not slowed cognitive decline. These observations argue against the amyloid hypothesis of AD etiology, its development, and disease mechanisms. Here, we look at other avenues in the research of AD, such as the presenilin hypothesis, synaptic glutamate signaling, and the role of astrocytes and the glutamate transporter EAAT2 in the development of AD.
Topics: Humans; Alzheimer Disease; Neurodegenerative Diseases; Amyloid beta-Peptides; Amyloid; Presenilins
PubMed: 36979388
DOI: 10.3390/biom13030453 -
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 -
Autophagy Sep 2022PSENEN/PEN2 is the smallest subunit of the γ-secretase complex, an intramembrane protease that cleaves proteins within their transmembrane domains. Mutations in...
PSENEN/PEN2 is the smallest subunit of the γ-secretase complex, an intramembrane protease that cleaves proteins within their transmembrane domains. Mutations in components of the γ-secretase underlie familial Alzheimer disease. In addition to its proteolytic activity, supplementary, γ-secretase independent, functions in the macroautophagy/autophagy-lysosome system have been proposed. Here, we screened for PSENEN-interacting proteins and identified CLN3. Mutations in are causative for juvenile neuronal ceroid lipofuscinosis, a rare lysosomal storage disorder considered the most common neurodegenerative disease in children. As mutations in the and genes cause different neurodegenerative diseases, understanding shared cellular functions of both proteins might be pertinent for understanding general cellular mechanisms underlying neurodegeneration. We hypothesized that CLN3 modulates γ-secretase activity and that PSENEN and CLN3 play associated roles in the autophagy-lysosome system. We applied CRISPR gene-editing and obtained independent isogenic HeLa knockout cell lines for and . Following previous studies, we demonstrate that PSENEN is essential for forming a functional γ-secretase complex and is indispensable for γ-secretase activity. In contrast, CLN3 does not modulate γ-secretase activity to a significant degree. We observed in - and -knockout cells corresponding alterations in the autophagy-lysosome system. These include reduced activity of lysosomal enzymes and lysosome number, an increased number of autophagosomes, increased lysosome-autophagosome fusion, and elevated levels of TFEB (transcription factor EB). Our study strongly suggests converging roles of PSENEN and CLN3 in the autophagy-lysosome system in a γ-secretase activity-independent manner, supporting the idea of common cytopathological processes underlying different neurodegenerative diseases. Aβ, amyloid-beta; AD, Alzheimer disease; APP, amyloid precursor protein; ATP5MC, ATP synthase membrane subunit c; DQ-BSA, dye-quenched bovine serum albumin; ER, endoplasmic reticulum; GFP, green fluorescent protein; ICC, immunocytochemistry; ICD, intracellular domain; JNCL, juvenile neuronal ceroid lipofuscinosis; KO, knockout; LC3, microtubule associated protein 1 light chain 3; NCL, neuronal ceroid lipofuscinoses; PSEN, presenilin; PSENEN/PEN2: presenilin enhancer, gamma-secretase subunit; TAP, tandem affinity purification; TEV, tobacco etch virus; TF, transferrin; WB, Western blot; WT, wild type.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Autophagy; Child; Humans; Lysosomes; Membrane Glycoproteins; Membrane Proteins; Molecular Chaperones; Neuronal Ceroid-Lipofuscinoses; Presenilins; Transcription Factors
PubMed: 34964690
DOI: 10.1080/15548627.2021.2016232 -
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 -
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 -
Seminars in Cell & Developmental Biology Apr 2009Over the years the presenilins (PSENs), a family of multi-transmembrane domain proteins, have been ascribed a number of diverse potential functions. Recent in vivo... (Review)
Review
Over the years the presenilins (PSENs), a family of multi-transmembrane domain proteins, have been ascribed a number of diverse potential functions. Recent in vivo evidence has supported the existence of PSEN functions beyond its well-established role in regulated intramembrane proteolysis. In this review, we will briefly discuss the ability of PSEN to modulate cellular signaling pathways through gamma-secretase cleavage of transmembrane proteins. Additionally, we will critically examine the proposed roles of PSEN in the regulation of beta-catenin function, protein trafficking, calcium regulation, and apoptosis.
Topics: Amyloid Precursor Protein Secretases; Humans; Membrane Proteins; Models, Biological; Presenilins; Protein Transport; Signal Transduction
PubMed: 19073272
DOI: 10.1016/j.semcdb.2008.11.014