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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 -
Nature Communications Oct 2022Inhibition of γ-secretase activity represents a potential therapeutic strategy for Alzheimer's disease (AD). MRK-560 is a selective inhibitor with higher potency for...
Inhibition of γ-secretase activity represents a potential therapeutic strategy for Alzheimer's disease (AD). MRK-560 is a selective inhibitor with higher potency for Presenilin 1 (PS1) than for PS2, the two isoforms of the catalytic subunit of γ-secretase, although the underlying mechanism remains elusive. Here we report the cryo-electron microscopy (cryo-EM) structures of PS1 and PS2-containing γ-secretase complexes with and without MRK-560 at overall resolutions of 2.9-3.4 Å. MRK-560 occupies the substrate binding site of PS1, but is invisible in PS2. Structural comparison identifies Thr281 and Leu282 in PS1 to be the determinant for isoform-dependent sensitivity to MRK-560, which is confirmed by swapping experiment between PS1 and PS2. By revealing the mechanism for isoform-selective inhibition of presenilin, our work may facilitate future drug discovery targeting γ-secretase.
Topics: Presenilin-1; Amyloid Precursor Protein Secretases; Presenilin-2; Cryoelectron Microscopy; Protein Isoforms
PubMed: 36272978
DOI: 10.1038/s41467-022-33817-5 -
Biochemistry. Biokhimiia Sep 2018The current issue is dedicated to the studies of neurodegenerative diseases and memory. Molecular mechanisms and mutant genes have already been revealed for many...
The current issue is dedicated to the studies of neurodegenerative diseases and memory. Molecular mechanisms and mutant genes have already been revealed for many neurodegenerative diseases. However, in many cases the cause of selective death of neurons in different brain regions remains unclear. Genetic predisposition and aging are well established risk factors in many neurodegenerative diseases. A large body of evidence has been obtained that shows an important role of immune factors in the modulation of neurodegenerative processes. The progress in the treatment of neurodegenerative diseases requires new cell models for identification of non-canonical pharmacological targets and development of approaches for memory regulation. Gene therapy technologies based on genome editing and RNA interference methods are among promising approaches for repairing primary molecular defects underlying neurodegenerative pathologies.
Topics: Amyloid beta-Protein Precursor; Brain; Genome-Wide Association Study; Humans; Mutation, Missense; Neurodegenerative Diseases; Neurons; Presenilin-1
PubMed: 30472938
DOI: 10.1134/S0006297918090018 -
Cold Spring Harbor Perspectives in... Dec 2017The presenilin proteins are the catalytic subunits of a tetrameric complex containing presenilin 1 or 2, anterior pharynx defective 1 (APH1), nicastrin, and PEN-2. Other... (Review)
Review
The presenilin proteins are the catalytic subunits of a tetrameric complex containing presenilin 1 or 2, anterior pharynx defective 1 (APH1), nicastrin, and PEN-2. Other components such as TMP21 may exist in a subset of specialized complexes. The presenilin complex is the founding member of a unique class of aspartyl proteases that catalyze the γ, ɛ, ζ site cleavage of the transmembrane domains of Type I membrane proteins including amyloid precursor protein (APP) and Notch. Here, we detail the structural and chemical biology of this unusual enzyme. Taken together, these studies suggest that the complex exists in several conformations, and subtle long-range (allosteric) shifts in the conformation of the complex underpin substrate access to the catalytic site and the mechanism of action for allosteric inhibitors and modulators. Understanding the mechanics of these shifts will facilitate the design of γ-secretase modulator (GSM) compounds that modulate the relative efficiency of γ, ɛ, ζ site cleavage and/or substrate specificity.
Topics: Amyloid beta-Protein Precursor; Animals; Humans; Presenilin-1; Presenilin-2
PubMed: 28320827
DOI: 10.1101/cshperspect.a024067 -
Theranostics 2021Mitochondrial dysfunction and oxidative stress are frequently observed in the early stages of Alzheimer's disease (AD). Studies have shown that presenilin-1 (PS1), the...
Mitochondrial dysfunction and oxidative stress are frequently observed in the early stages of Alzheimer's disease (AD). Studies have shown that presenilin-1 (PS1), the catalytic subunit of γ-secretase whose mutation is linked to familial AD (FAD), localizes to the mitochondrial membrane and regulates its homeostasis. Thus, we investigated how five mutations (A431E, E280A, H163R, M146V, and Δexon9) observed in FAD affect mitochondrial functions. We used H4 glioblastoma cell lines genetically engineered to inducibly express either the wild-type PS1 or one of the five PS1 mutants in order to examine mitochondrial morphology, dynamics, membrane potential, ATP production, mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), oxidative stress, and bioenergetics. Furthermore, we used brains of PS1M146V knock-in mice, 3xTg-AD mice, and human AD patients in order to investigate the role of PS1 in regulating MAMs formation. Each PS1 mutant exhibited slightly different mitochondrial dysfunction. Δexon9 mutant induced mitochondrial fragmentation while A431E, E280A, H163R, and M146V mutants increased MAMs formation. A431E, E280A, M146V, and Δexon9 mutants also induced mitochondrial ROS production. A431E mutant impaired both complex I and peroxidase activity while M146V mutant only impaired peroxidase activity. All PS1 mutants compromised mitochondrial membrane potential and cellular ATP levels were reduced by A431E, M146V, and Δexon9 mutants. Through comparative profiling of hippocampal gene expression in PS1M146V knock-in mice, we found that PS1M146V upregulates Atlastin 2 (ATL2) expression level, which increases ER-mitochondria contacts. Down-regulation of ATL2 after PS1 mutant induction rescued abnormally elevated ER-mitochondria interactions back to the normal level. Moreover, ATL2 expression levels were significantly elevated in the brains of 3xTg-AD mice and AD patients. Overall, our findings suggest that each of the five FAD-linked mutations has a deleterious effect on mitochondrial functions in a variety of ways. The adverse effects of PS1 mutations on mitochondria may contribute to MAMs formation and oxidative stress resulting in an accelerated age of disease onset in people harboring mutant PS1.
Topics: Adenosine Triphosphate; Alzheimer Disease; Animals; Cell Line, Tumor; Endoplasmic Reticulum; Gene Knock-In Techniques; Humans; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Mutation; Oxidative Stress; Presenilin-1
PubMed: 34522215
DOI: 10.7150/thno.59776 -
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 -
Cells Sep 2020Presenilin-2 (PS2) is one of the three proteins that are dominantly mutated in familial Alzheimer's disease (FAD). It forms the catalytic core of the γ-secretase... (Review)
Review
Presenilin-2 (PS2) is one of the three proteins that are dominantly mutated in familial Alzheimer's disease (FAD). It forms the catalytic core of the γ-secretase complex-a function shared with its homolog presenilin-1 (PS1)-the enzyme ultimately responsible of amyloid-β (Aβ) formation. Besides its enzymatic activity, PS2 is a multifunctional protein, being specifically involved, independently of γ-secretase activity, in the modulation of several cellular processes, such as Ca signalling, mitochondrial function, inter-organelle communication, and autophagy. As for the former, evidence has accumulated that supports the involvement of PS2 at different levels, ranging from organelle Ca handling to Ca entry through plasma membrane channels. Thus FAD-linked PS2 mutations impact on multiple aspects of cell and tissue physiology, including bioenergetics and brain network excitability. In this contribution, we summarize the main findings on PS2, primarily as a modulator of Ca homeostasis, with particular emphasis on the role of its mutations in the pathogenesis of FAD. Identification of cell pathways and molecules that are specifically targeted by PS2 mutants, as well as of common targets shared with PS1 mutants, will be fundamental to disentangle the complexity of memory loss and brain degeneration that occurs in Alzheimer's disease (AD).
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Brain; Calcium; Calcium Signaling; Cell Membrane; Flavin-Adenine Dinucleotide; Humans; Multiprotein Complexes; Mutant Proteins; Presenilin-1; Presenilin-2
PubMed: 32992716
DOI: 10.3390/cells9102166 -
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 -
The Journal of Experimental Medicine Nov 2017The blood-brain barrier (BBB) keeps neurotoxic plasma-derived components, cells, and pathogens out of the brain. An early BBB breakdown and/or dysfunction have been... (Review)
Review
The blood-brain barrier (BBB) keeps neurotoxic plasma-derived components, cells, and pathogens out of the brain. An early BBB breakdown and/or dysfunction have been shown in Alzheimer's disease (AD) before dementia, neurodegeneration and/or brain atrophy occur. However, the role of BBB breakdown in neurodegenerative disorders is still not fully understood. Here, we examine BBB breakdown in animal models frequently used to study the pathophysiology of AD, including transgenic mice expressing human amyloid-β precursor protein, presenilin 1, and tau mutations, and apolipoprotein E, the strongest genetic risk factor for AD. We discuss the role of BBB breakdown and dysfunction in neurodegenerative process, pitfalls in BBB measurements, and how targeting the BBB can influence the course of neurological disorder. Finally, we comment on future approaches and models to better define, at the cellular and molecular level, the underlying mechanisms between BBB breakdown and neurodegeneration as a basis for developing new therapies for BBB repair to control neurodegeneration.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Blood-Brain Barrier; Disease Models, Animal; Humans; Mice, Transgenic; Mutation; Presenilin-1; tau Proteins
PubMed: 29061693
DOI: 10.1084/jem.20171406 -
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