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International Journal of Molecular... Feb 2024Presenilin, a transmembrane protein primarily known for its role in Alzheimer's disease (AD) as part of the γ-secretase complex, has garnered increased attention due to... (Review)
Review
Presenilin, a transmembrane protein primarily known for its role in Alzheimer's disease (AD) as part of the γ-secretase complex, has garnered increased attention due to its multifaceted functions in various cellular processes. Recent investigations have unveiled a plethora of functions beyond its amyloidogenic role. This review aims to provide a comprehensive overview of presenilin's diverse roles in AD and other neurodegenerative disorders. It includes a summary of well-known substrates of presenilin, such as its involvement in amyloid precursor protein (APP) processing and Notch signaling, along with other functions. Additionally, it highlights newly discovered functions, such as trafficking function, regulation of ferritin expression, apolipoprotein E (ApoE) secretion, the interaction of ApoE and presenilin, and the Aβ42-to-Aβ40-converting activity of ACE. This updated perspective underscores the evolving landscape of presenilin research, emphasizing its broader impact beyond established pathways. The incorporation of these novel findings accentuates the dynamic nature of presenilin's involvement in cellular processes, further advancing our comprehension of its multifaceted roles in neurodegenerative disorders. By synthesizing evidence from a range of studies, this review sheds light on the intricate web of presenilin functions and their implications in health and disease.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Neurodegenerative Diseases; Amyloid Precursor Protein Secretases; Presenilin-1; Amyloid beta-Protein Precursor; Apolipoproteins E; Presenilin-2
PubMed: 38339035
DOI: 10.3390/ijms25031757 -
Expert Reviews in Molecular Medicine Aug 2002Familial Alzheimer's disease (FAD) accounts for 5-10% of deaths from Alzheimer's disease (AD), and approximately 50% of these cases have been definitely linked to... (Review)
Review
Familial Alzheimer's disease (FAD) accounts for 5-10% of deaths from Alzheimer's disease (AD), and approximately 50% of these cases have been definitely linked to missense mutations in three genes, encoding the amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2). Of these, the vast majority of FAD-linked mutations are within PS1. There has been an extensive effort to identify proteins that functionally interact with PS1 and PS2 because of their clear roles in FAD. The goal of this review is to describe these proteins and to discuss in more detail the probable biological functions of a subset of the better-studied interacting proteins. In particular, the review examines APP, Notch, nicastrin, modifier of cellular adhesion (MOCA), beta-catenin, and the group of proteins involved in cell death, calcium metabolism and cell adhesion. We argue that, although a few of the interacting proteins are unambiguously involved in well-studied cellular pathways, their exact roles within these pathways have not been clearly defined, and indeed might vary between cell types. We also question the physiological relevance of some of the work linking PS to cell death pathways. Finally, we point out the value of using flies and worms to sort out the often contradictory work in the PS field, and we mention how knowledge of PS-interacting pathways will contribute to the development of new therapeutic strategies in AD.
Topics: Alzheimer Disease; Animals; Humans; Membrane Proteins; Presenilin-1; Presenilin-2; Protein Interaction Mapping
PubMed: 14585160
DOI: 10.1017/S1462399402005008 -
Seminars in Cell & Developmental Biology Sep 2020The intramembrane protease γ-secretase is a hetero-tetrameric protein complex with presenilin as the catalytic subunit and cleaves its membrane protein substrates... (Review)
Review
The intramembrane protease γ-secretase is a hetero-tetrameric protein complex with presenilin as the catalytic subunit and cleaves its membrane protein substrates within their single transmembrane domains. γ-Secretase is well known for its role in Notch signalling and in Alzheimer's disease, where it catalyzes the formation of the pathogenic amyloid β (Aβ) peptide. However, in the 21 years since its discovery many more substrates and substrate candidates of γ-secretase were identified. Although the physiological relevance of the cleavage of many substrates remains to be studied in more detail, the substrates demonstrate a broad role for γ-secretase in embryonic development, adult tissue homeostasis, signal transduction and protein degradation. Consequently, chronic γ-secretase inhibition may cause significant side effects due to inhibition of cleavage of multiple substrates. This review provides a list of 149 γ-secretase substrates identified to date and highlights by which expeirmental approach substrate cleavage was validated. Additionally, the review lists the cleavage sites where they are known and discusses the functional implications of γ-secretase cleavage with a focus on substrates identified in the recent past, such as CHL1, TREM2 and TNFR1. A comparative analysis demonstrates that γ-secretase substrates mostly have a long extracellular domain and require ectodomain shedding before γ-secretase cleavage, but that γ-secretase is also able to cleave naturally short substrates, such as the B cell maturation antigen. Taken together, the list of substrates provides a resource that may help in the future development of drugs inhibiting or modulating γ-secretase activity in a substrate-specific manner.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Humans; Presenilins; Signal Transduction
PubMed: 32616437
DOI: 10.1016/j.semcdb.2020.05.019 -
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 -
Seminars in Cell & Developmental Biology Sep 2020Genetic research on familial cases of Alzheimer disease have identified presenilin (PS) as an important membrane protein in the pathomechanism of this disease. PS is the... (Review)
Review
Genetic research on familial cases of Alzheimer disease have identified presenilin (PS) as an important membrane protein in the pathomechanism of this disease. PS is the catalytic subunit of γ-secretase, which is responsible for the generation of amyloid-β peptide deposited in the brains of Alzheimer disease patients. γ-Secretase is an atypical protease composed of four membrane proteins (i.e., presenilin, nicastrin, anterior pharynx defective-1 (Aph-1), and presenilin enhancer-2 (Pen-2)) and mediates intramembrane proteolysis. Numerous investigations have been conducted toward understanding the structural features of γ-secretase components as well as the cleavage mechanism of γ-secretase. In this review, we summarize our current understanding of the structure and activity relationship of the γ-secretase complex.
Topics: Amyloid Precursor Protein Secretases; Humans; Membrane Proteins; Presenilins; Structure-Activity Relationship
PubMed: 32171519
DOI: 10.1016/j.semcdb.2020.02.006 -
Physiology & Behavior Sep 2007Presenilin proteins, mutated forms of which cause early onset familial Alzheimer's disease, are capable of modulating various cell signal transduction pathways, the most... (Review)
Review
Presenilin proteins, mutated forms of which cause early onset familial Alzheimer's disease, are capable of modulating various cell signal transduction pathways, the most extensively studied of which has been intracellular calcium signalling. Disease causing presenilin mutations can potentiate inositol(1,4,5)trisphosphate (InsP3) mediated endoplasmic reticulum release due to calcium overload in this organelle, as well as attenuate capacitative calcium entry. Our own studies have shown a novel function for presenilins that involves regulation of acetylcholine muscarinic receptor-stimulated phospholipase C upstream of InsP3 regulated calcium release. This article reviews the mechanisms by which presenilins modulate intracellular calcium signalling and the role that deregulated calcium homeostasis could play in the pathogenesis of Alzheimer's disease.
Topics: Alzheimer Disease; Animals; Calcium Signaling; Humans; Presenilins; Signal Transduction; Type C Phospholipases
PubMed: 17568632
DOI: 10.1016/j.physbeh.2007.05.053 -
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 -
Progress in Neurobiology Feb 2011Autosomal dominant mutations in the presenilin gene PSEN cause familial Alzheimer's disease (AD), a neurological disorder pathologically characterized by intraneuronal... (Review)
Review
Autosomal dominant mutations in the presenilin gene PSEN cause familial Alzheimer's disease (AD), a neurological disorder pathologically characterized by intraneuronal accumulation and extracellular deposition of amyloid-β in plaques and intraneuronal, hyperphosphorylated tau aggregation in neurofibrillary tangles. Presenilins (PS/PSENs) are part of the proteolytic γ-secretase complex, which cleaves substrate proteins within the membrane. Cleavage of the amyloid precursor protein (APP) by γ-secretase releases amyloid-β peptides. Besides its role in the processing of APP and other transmembrane proteins, presenilin plays an important role in neural progenitor cell maintenance and neurogenesis. In this review, we discuss the role of presenilin in relation to neurogenesis and neurodegeneration and review the currently available presenilin animal models. In addition to established mouse models, zebrafish are emerging as an attractive vertebrate model organism to study the role of presenilin during the development of the nervous system and in neurodegenerative disorders involving presenilin. Zebrafish is a suitable model organism for large-scale drug screening, making this a valuable model to identify novel therapeutic targets for AD.
Topics: Amyloid Precursor Protein Secretases; Animals; Dementia; Disease Models, Animal; Humans; Mice; Mutation; Neurogenesis; Presenilins; Protein Isoforms; Zebrafish
PubMed: 21056616
DOI: 10.1016/j.pneurobio.2010.10.008 -
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 -
Cellular and Molecular Life Sciences :... May 2009Inhibiting the production of amyloid-beta by antagonising gamma-secretase activity is currently being pursued as a therapeutic strategy for Alzheimer's disease (AD).... (Review)
Review
Inhibiting the production of amyloid-beta by antagonising gamma-secretase activity is currently being pursued as a therapeutic strategy for Alzheimer's disease (AD). However, early pre-clinical studies have demonstrated that disruption of presenilin-dependent gamma-secretase alters many presenilin-dependent processes, leading to early lethality in several AD model organisms. Subsequently, transgenic animal studies have highlighted several gross developmental side effects arising from presenilin deficiency. Partial knockdown or tissue-specific knockout of presenilins has identified the skin, vascular and immune systems as very sensitive to loss of presenilin functions. A more appreciative understanding of presenilin biology is therefore demanded if gamma-secretase is to be pursued as a therapeutic target. Herein we review the current understanding of gamma-secretase complexes; their regulation, abundance of interacting partners and diversity of substrates. We also discuss regulation of the gamma-secretase complexes, with an emphasis on the functional role of presenilins in cell biology.
Topics: Amyloid Precursor Protein Secretases; Animals; Models, Biological; Presenilins; Signal Transduction; Substrate Specificity
PubMed: 19189053
DOI: 10.1007/s00018-009-8435-9