-
Neuroscience Letters Jan 2016Alzheimer's disease (AD) is a neurodegenerative disease affecting over 20 million people worldwide, mainly adult subjects in advanced age. Over 240 different fully...
Alzheimer's disease (AD) is a neurodegenerative disease affecting over 20 million people worldwide, mainly adult subjects in advanced age. Over 240 different fully penetrant autosomal dominant mutations in 532 families around the world have been described in three genes [i.e., amyloid precursor protein (APP), and presenilins (PSEN1 and PSEN2)] causing 50% of all Familial AD. We report a new mutation (p.Ile408Thr, c. 1223T>C) in the PSEN1 gene in one autosomal dominant Late Onset AD patient. The genetic variation occurred in a conserved domain of the protein and was present in the proband and in the younger sister who is likely to be prodromal AD. Thus, we suggest that this variant will have probably a pathogenic effect, hypothesizing a possible key role of this new mutation in the pathogenesis of Alzheimer's disease for this family.
Topics: Age of Onset; Aged; Aged, 80 and over; Alzheimer Disease; Female; Humans; Mutation; Pedigree; Presenilin-1
PubMed: 26549787
DOI: 10.1016/j.neulet.2015.11.004 -
ENeuro 2021Mutations in the genes (, ) have been linked to the majority of familial Alzheimer's disease (AD). Although great efforts have been made to investigate pathogenic...
Mutations in the genes (, ) have been linked to the majority of familial Alzheimer's disease (AD). Although great efforts have been made to investigate pathogenic mutations, which ultimately cause an increase in the toxic form of β-amyloid (Aβ), the intrinsic physiological functions of PS in human neurons remain to be determined. In this study, to investigate the physiological roles of PS in human neurons, we generated conditional knock-out (KO) induced pluripotent stem cells (iPSCs), in which PS1 can be selectively abrogated under Cre transduction with or without additional KO. We showed that iPSC-derived neural progenitor cells (NPCs) do not confer a maintenance ability in the absence of both PS1 and PS2, showing the essential role of PS in Notch signaling. We then generated -null human cortical neurons, where PS1 was intact until full neuronal differentiation occurred. Aβ40 production was reduced exclusively in human /-null neurons along with a concomitant accumulation of amyloid β precursor protein (APP)-C-terminal fragments CTFs, whereas Aβ42 was decreased in neurons devoid of Unlike previous studies in mice, in which APP cleavage is largely attributable to PS1, γ-secretase activity seemed to be comparable between PS1 and PS2. In contrast, cleavage of another substrate, N-cadherin, was impaired only in neurons devoid of Moreover, PS2/γ-secretase exists largely in late endosomes/lysosomes, as measured by specific antibody against the γ-secretase complex, in which Aβ42 species are supposedly produced. Using this novel stem cell-based platform, we assessed important physiological PS1/PS2 functions in mature human neurons, the dysfunction of which could underlie AD pathogenesis.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Humans; Mice; Neurons; Presenilin-1; Presenilin-2
PubMed: 33608391
DOI: 10.1523/ENEURO.0500-20.2021 -
Experimental Neurology Mar 2023Patients with early-onset Alzheimer's disease (EOAD) are at elevated risk for seizures, including patients with presenilin 2 (PSEN2) variants. Like people with epilepsy,...
Patients with early-onset Alzheimer's disease (EOAD) are at elevated risk for seizures, including patients with presenilin 2 (PSEN2) variants. Like people with epilepsy, uncontrolled seizures may worsen cognitive function in AD. While the relationship between seizures and amyloid beta accumulation has been more thoroughly investigated, the role of other drivers of seizure susceptibility in EOAD remain relatively understudied. We therefore sought to define the impact of loss of normal PSEN2 function and chronic seizures on cognitive function in the aged brain. Male and female PSEN2 KO and age- and sex-matched wild-type (WT) mice were sham or corneal kindled beginning at 6-months-old. Kindled and sham-kindled mice were then challenged up to 6 weeks later in a battery of cognitive tests: non-habituated open field (OF), T-maze spontaneous alternation (TM), and Barnes maze (BM), followed by immunohistochemistry for markers of neuroinflammation and neuroplasticity. PSEN2 KO mice required significantly more stimulations to kindle (males: p < 0.02; females: p < 0.02) versus WT. Across a range of behavioral tests, the cognitive performance of kindled female PSEN2 KO mice was most significantly impaired versus age-matched WT females. Male BM performance was generally worsened by seizures (p = 0.038), but loss of PSEN2 function did not itself worsen cognitive performance. Conversely, kindled PSEN2 KO females made the most BM errors (p = 0.007). Chronic seizures also significantly altered expression of hippocampal neuroinflammation and neuroplasticity markers in a sex-specific manner. Chronic seizures may thus significantly worsen hippocampus-dependent cognitive deficits in aged female, but not male, PSEN2 KO mice. Our work suggests that untreated focal seizures may worsen cognitive burden with loss of normal PSEN2 function in a sex-related manner.
Topics: Male; Mice; Female; Animals; Amyloid beta-Peptides; Presenilin-2; Neuroinflammatory Diseases; Seizures; Alzheimer Disease; Cognition; Presenilin-1
PubMed: 36634751
DOI: 10.1016/j.expneurol.2023.114321 -
Neurology Mar 2010
Topics: Alzheimer Disease; Humans; Mutation; Presenilins
PubMed: 20164096
DOI: 10.1212/WNL.0b013e3181d3e429 -
PloS One 2022The most commonly accepted hypothesis of Alzheimer's disease (AD) is the amyloid hypothesis caused due to formation of accumulation of Aβ42 isoform, which leads to...
The most commonly accepted hypothesis of Alzheimer's disease (AD) is the amyloid hypothesis caused due to formation of accumulation of Aβ42 isoform, which leads to neurodegeneration. In this regard, presenilin-1 (PSEN-1) and -2 (PSEN-2) proteins play a crucial role by altering the amyloid precursor protein (APP) metabolism, affecting γ-secretase protease secretion, finally leading to the increased levels of Aβ. In the absence of reported commercial pharmacotherapeutic agents targeting presenilins, we aim to propose benzophenone integrated derivatives (BIDs) as the potential inhibitors of presenilin proteins through in silico approach. The study evaluates the interaction of BIDs through molecular docking simulations, molecular dynamics simulations, and binding free energy calculations. This is the first ever computational approach to discover the potential inhibitors of presenilin proteins. It also comprises druglikeliness and pharmacotherapeutic potential analysis of the compounds. Out of all the screened BIDs, BID-16 was found to be the lead compound against both the presenilin proteins. Based on these results, one can evaluate BID-16 as an anti-Alzheimer's potential specifically targeting presenilin proteins in near future using in vitro and in vivo methods.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Benzophenones; Humans; Molecular Docking Simulation; Presenilin-1; Presenilin-2
PubMed: 35395008
DOI: 10.1371/journal.pone.0265022 -
PloS One 2012The intramembrane-cleaving protease γ-secretase catalyzes the last step in the generation of toxic amyloid-β (Aβ) peptides and is a principal therapeutic target in...
The intramembrane-cleaving protease γ-secretase catalyzes the last step in the generation of toxic amyloid-β (Aβ) peptides and is a principal therapeutic target in Alzheimer's disease. Both preclinical and clinical studies have demonstrated that inhibition of γ-secretase is associated with prohibitive side effects due to suppression of Notch processing and signaling. Potentially safer are γ-secretase modulators (GSMs), which are small molecules that selectively lower generation of the highly amyloidogenic Aβ42 peptides but spare Notch processing. GSMs with nanomolar potency and favorable pharmacological properties have been described, but the molecular mechanism of GSMs remains uncertain and both the substrate amyloid precursor protein (APP) and subunits of the γ-secretase complex have been proposed as the molecular target of GSMs. We have generated a potent photo-probe based on an acidic GSM that lowers Aβ42 generation with an IC(50) of 290 nM in cellular assays. By combining in vivo photo-crosslinking with affinity purification, we demonstrated that this probe binds the N-terminal fragment of presenilin (PSEN), the catalytic subunit of the γ-secretase complex, in living cells. Labeling was not observed for APP or any of the other γ-secretase subunits. Binding was readily competed by structurally divergent acidic and non-acidic GSMs suggesting a shared mode of action. These findings indicate that potent acidic GSMs target presenilin to modulate the enzymatic activity of the γ-secretase complex.
Topics: Amyloid Precursor Protein Secretases; Animals; Anti-Inflammatory Agents, Non-Steroidal; CHO Cells; Cells; Cells, Cultured; Cricetinae; Cricetulus; Drug Evaluation, Preclinical; Enzyme Inhibitors; HEK293 Cells; Humans; Inhibitory Concentration 50; Models, Biological; Molecular Targeted Therapy; Presenilins
PubMed: 22238696
DOI: 10.1371/journal.pone.0030484 -
Progress in Neurobiology Nov 2020Synaptic loss is the best correlate of cognitive deficits in Alzheimer's disease (AD). Extensive experimental evidence also indicates alterations of synaptic properties... (Review)
Review
Synaptic loss is the best correlate of cognitive deficits in Alzheimer's disease (AD). Extensive experimental evidence also indicates alterations of synaptic properties at the early stages of disease progression, before synapse loss and neuronal degeneration. A majority of studies in mouse models of AD have focused on post-synaptic mechanisms, including impairment of long-term plasticity, spine structure and glutamate receptor-mediated transmission. Here we review the literature indicating that the synaptic pathology in AD includes a strong presynaptic component. We describe the evidence indicating presynaptic physiological functions of the major molecular players in AD. These include the amyloid precursor protein (APP) and the two presenilin (PS) paralogs PS1 or PS2, genetically linked to the early-onset form of AD, in addition to tau which accumulates in a pathological form in the AD brain. Three main mechanisms participating in presynaptic functions are highlighted. APP fragments bind to presynaptic receptors (e.g. nAChRs and GABA receptors), presenilins control Ca homeostasis and Ca-sensors, and tau regulates the localization of presynaptic molecules and synaptic vesicles. We then discuss how impairment of these presynaptic physiological functions can explain or forecast the hallmarks of synaptic impairment and associated dysfunction of neuronal circuits in AD. Beyond the physiological roles of the AD-related proteins, studies in AD brains also support preferential presynaptic alteration. This review features presynaptic failure as a strong component of pathological mechanisms in AD.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Humans; Presenilins; Presynaptic Terminals; Receptors, Presynaptic; Synaptic Transmission; tau Proteins
PubMed: 32428558
DOI: 10.1016/j.pneurobio.2020.101801 -
The Journal of Biological Chemistry Mar 2015Understanding the molecular mechanisms controlling the physiological and pathological activity of γ-secretase represents a challenging task in Alzheimer disease...
Understanding the molecular mechanisms controlling the physiological and pathological activity of γ-secretase represents a challenging task in Alzheimer disease research. The assembly and proteolytic activity of this enzyme require the correct interaction of the 19 transmembrane domains (TMDs) present in its four subunits, including presenilin (PS1 or PS2), the γ-secretase catalytic core. GXXXG and GXXXG-like motifs are critical for TMDs interactions as well as for protein folding and assembly. The GXXXG motifs on γ-secretase subunits (e.g. APH-1) or on γ-secretase substrates (e.g. APP) are known to be involved in γ-secretase assembly and in Aβ peptide production, respectively. We identified on PS1 and PS2 TMD8 two highly conserved AXXXAXXXG motifs. The presence of a mutation causing an inherited form of Alzheimer disease (familial Alzheimer disease) in the PS1 motif suggested their involvement in the physiopathological configuration of the γ-secretase complex. In this study, we targeted the role of these motifs on TMD8 of PSs, focusing on their role in PS assembly and catalytic activity. Each motif was mutated, and the impact on complex assembly, activity, and substrate docking was monitored. Different amino acid substitutions on the same motif resulted in opposite effects on γ-secretase activity, without affecting the assembly or significantly impairing the maturation of the complex. Our data suggest that AXXXAXXXG motifs in PS TMD8 are key determinants for the conformation of the mature γ-secretase complex, participating in the switch between the physiological and pathological functional conformations of the γ-secretase.
Topics: Amino Acid Sequence; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Animals; CHO Cells; Cell Line; Conserved Sequence; Cricetulus; HEK293 Cells; Humans; Mice; Molecular Sequence Data; Mutation; Presenilin-1; Presenilin-2; Protein Structure, Tertiary
PubMed: 25614624
DOI: 10.1074/jbc.M114.601286 -
Methods in Enzymology 2017Presenilin is a catalytic subunit of γ-secretase, which hydrolyzes several transmembrane proteins within the lipid bilayer, together with binding cofactors such as...
Presenilin is a catalytic subunit of γ-secretase, which hydrolyzes several transmembrane proteins within the lipid bilayer, together with binding cofactors such as nicastrin, Aph-1, and Pen-2. However, the structural basis as well as molecular mechanism of this unusual proteolytic process remains unknown. We have analyzed the structure and function relationships of presenilin using the substituted-cysteine accessibility method (SCAM), which enables identification of the hydrophilic environment by the accessibility of sulfhydryl reagents to cysteine residues introduced at a desired position. In combination with small molecule inhibitors/modulators and cross-linking experiments, we were able to identify certain residues and regions of presenilin that contribute to its intramembrane-cleaving activity. In addition, we revealed the structural dynamics of the transmembrane domains of presenilin during the formation of the complex and its proteolytic process. The SCAM provides new insights into the relationship between the structure and activity of presenilin, and is useful for probing the protein dynamics of the membrane-embedded enzymes.
Topics: Amino Acid Substitution; Amyloid Precursor Protein Secretases; Catalytic Domain; Cysteine; Enzyme Inhibitors; Humans; Hydrophobic and Hydrophilic Interactions; Lipid Bilayers; Molecular Biology; Presenilins; Protein Domains; Protein Structure, Tertiary; Small Molecule Libraries; Structure-Activity Relationship
PubMed: 28065263
DOI: 10.1016/bs.mie.2016.10.033 -
FASEB Journal : Official Publication of... Jan 2024γ-secretase processing of amyloid precursor protein (APP) has long been of interest in the pathological progression of Alzheimer's disease (AD) due to its role in the...
γ-secretase processing of amyloid precursor protein (APP) has long been of interest in the pathological progression of Alzheimer's disease (AD) due to its role in the generation of amyloid-β. The catalytic component of the enzyme is the presenilins of which there are two homologues, Presenilin-1 (PS1) and Presenilin-2 (PS2). The field has focussed on the PS1 form of this enzyme, as it is typically considered the more active at APP processing. However, much of this work has been completed without appropriate consideration of the specific levels of protein expression of PS1 and PS2. We propose that expression is an important factor in PS1- and PS2-γ-secretase activity, and that when this is considered, PS1 does not have greater activity than PS2. We developed and validated tools for quantitative assessment of PS1 and PS2 protein expression levels to enable the direct comparison of PS in exogenous and endogenous expression systems, in HEK-293 PS1 and/or PS2 knockout cells. We show that exogenous expression of Myc-PS1-NTF is 5.5-times higher than Myc-PS2-NTF. Quantitating endogenous PS protein levels, using a novel PS1/2 fusion standard we developed, showed similar results. When the marked difference in PS1 and PS2 protein levels is considered, we show that compared to PS1-γ-secretase, PS2-γ-secretase has equal or more activity on APP and Notch1. This study has implications for understanding the PS1- and PS2-specific contributions to substrate processing, and their potential influence in AD pathogenesis.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Endopeptidases; HEK293 Cells; Presenilin-1; Presenilin-2
PubMed: 38156414
DOI: 10.1096/fj.202300954RR