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International Journal of Molecular... Jan 2023In Alzheimer's disease (AD), the reduction in acetylcholinesterase (AChE) enzymatic activity is not paralleled with changes in its protein levels, suggesting the...
In Alzheimer's disease (AD), the reduction in acetylcholinesterase (AChE) enzymatic activity is not paralleled with changes in its protein levels, suggesting the presence of a considerable enzymatically inactive pool in the brain. In the present study, we validated previous findings, and, since inactive forms could result from post-translational modifications, we analyzed the glycosylation of AChE by lectin binding in brain samples from sporadic and familial AD (sAD and fAD). Most of the enzymatically active AChE was bound to lectins (Con A) and (LCA) that recognize terminal mannoses, whereas Western blot assays showed a very low percentage of AChE protein being recognized by the lectin. This indicates that active and inactive forms of AChE vary in their glycosylation pattern, particularly in the presence of terminal mannoses in active ones. Moreover, sAD subjects showed reduced binding to terminal mannoses compared to non-demented controls, while, for fAD patients that carry mutations in the PSEN1 gene, the binding was higher. The role of presenilin-1 (PS1) in modulating AChE glycosylation was then studied in a cellular model that overexpresses PS1 (CHO-PS1). In CHO-PS1 cells, binding to LCA indicates that AChE displays more terminal mannoses in oligosaccharides with a fucosylated core. Immunocytochemical assays also demonstrated increased presence of AChE in the trans-Golgi. Moreover, AChE enzymatic activity was higher in plasmatic membrane of CHO-PS1 cells. Thus, our results indicate that PS1 modulates trafficking and maturation of AChE in Golgi regions favoring the presence of active forms in the membrane.
Topics: Cricetinae; Animals; Humans; Acetylcholinesterase; Presenilin-1; Alzheimer Disease; Lectins; Brain; Cricetulus; Presenilin-2; Mutation
PubMed: 36674948
DOI: 10.3390/ijms24021437 -
Biochimica Et Biophysica Acta Jul 2000Numerous missense mutations in the presenilins are associated with the autosomal dominant form of familial Alzheimer disease. Presenilin genes encode polytopic... (Review)
Review
Numerous missense mutations in the presenilins are associated with the autosomal dominant form of familial Alzheimer disease. Presenilin genes encode polytopic transmembrane proteins, which are processed by proteolytic cleavage and form high-molecular-weight complexes under physiological conditions. The presenilins have been suggested to be functionally involved in developmental morphogenesis, unfolded protein responses and processing of selected proteins including the beta-amyloid precursor protein. Although the underlying mechanism by which presenilin mutations lead to development of Alzheimer disease remains elusive, one consistent mutational effect is an overproduction of long-tailed amyloid beta-peptides. Furthermore, presenilins interact with beta-catenin to form presenilin complexes, and the physiological and mutational effects are also observed in the catenin signal transduction pathway.
Topics: Alzheimer Disease; Amino Acid Sequence; Animals; Binding Sites; Cell Membrane; Cytoskeletal Proteins; Hippocampus; Humans; Membrane Proteins; Models, Molecular; Molecular Sequence Data; Mutation; Presenilin-1; Presenilin-2; Signal Transduction; Trans-Activators; beta Catenin
PubMed: 10899427
DOI: 10.1016/s0925-4439(00)00028-4 -
Proceedings of the National Academy of... Sep 2013
Topics: Animals; Hippocampus; Presenilin-1; Presenilin-2; Ryanodine Receptor Calcium Release Channel
PubMed: 23995445
DOI: 10.1073/pnas.1313996110 -
The Journal of Neuroscience : the... Jan 2022Presenilin (PSEN)/γ-secretase is a protease complex responsible for the proteolytic processing of numerous substrates. These substrates include the amyloid precursor...
Presenilin (PSEN)/γ-secretase is a protease complex responsible for the proteolytic processing of numerous substrates. These substrates include the amyloid precursor protein (APP), the cleavage of which by γ-secretase results in the production of β-amyloid (Aβ) peptides. However, exactly where within the neuron γ-secretase processes APP C99 to generate Aβ and APP intracellular domain (AICD) is still not fully understood. Here, we employ novel Förster resonance energy transfer (FRET)-based multiplexed imaging assays to directly "visualize" the subcellular compartment(s) in which γ-secretase primarily cleaves C99 in mouse cortex primary neurons (from both male and female embryos). Our results demonstrate that γ-secretase processes C99 mainly in LysoTracker-positive low-pH compartments. Using a new immunostaining protocol which distinguishes Aβ from C99, we also show that intracellular Aβ is significantly accumulated in the same subcellular loci. Furthermore, we found functional correlation between the endo-lysosomal pH and cellular γ-secretase activity. Taken together, our findings are consistent with Aβ being produced from C99 by γ-secretase within acidic compartments such as lysosomes and late endosomes in living neurons. Alzheimer's disease (AD) genetics and histopathology highlight the importance of amyloid precursor protein (APP) processing by γ-secretase in pathogenesis. For the first time, this study has enabled us to directly "visualize" that γ-secretase processes C99 mainly in acidic compartments such as late endosomes and lysosomes in live neurons. Furthermore, we uncovered that intracellular β-amyloid (Aβ) is significantly accumulated in the same subcellular loci. Emerging evidence proposes the great importance of the endo-lysosomal pathway in mechanisms of misfolded proteins propagation (e.g., Tau, α-Syn). Therefore, the predominant processing of C99 and enrichment of Aβ in late endosomes and lysosomes may be critical events in the molecular cascade leading to AD.
Topics: Amyloid Precursor Protein Secretases; Amyloid beta-Protein Precursor; Animals; Endosomes; Female; Lysosomes; Male; Mice; Neurons; Presenilins
PubMed: 34810230
DOI: 10.1523/JNEUROSCI.1698-21.2021 -
Trends in Genetics : TIG Mar 2007Presenilin, the catalytic member of the gamma-secretase proteolytic complex, was discovered through its roles in generating Alzheimer's-disease-associated amyloid-beta... (Review)
Review
Presenilin, the catalytic member of the gamma-secretase proteolytic complex, was discovered through its roles in generating Alzheimer's-disease-associated amyloid-beta peptides from the amyloid-beta precursor protein and in releasing the transcriptionally active domain of the receptor Notch. Recent work has revealed many additional cleavage substrates and interacting proteins, suggesting a diversity of roles for presenilin during development and adult life, some of which might contribute to Alzheimer's disease progression. Although many of these functions depend on the proteolytic activity of gamma-secretase, others are independent of its role as a protease. Here, we review recent data on candidate functions for presenilin and its interactors and on their potential significance in disease.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Calcium; Cell Adhesion; Humans; Nerve Tissue Proteins; Phosphorylation; Presenilins; Signal Transduction; Substrate Specificity; Transcription, Genetic; tau Proteins
PubMed: 17280736
DOI: 10.1016/j.tig.2007.01.008 -
Archives of Insect Biochemistry and... Apr 2022Disruption of the presenilin (ps) genes are the major genetic cause of familial Alzheimer's disease. The silkworm, Bombyx mori (B. mori), is an important model insect....
Disruption of the presenilin (ps) genes are the major genetic cause of familial Alzheimer's disease. The silkworm, Bombyx mori (B. mori), is an important model insect. The ps homologue gene in B. mori was identified and characterized. However, the role of ps in B. mori was poorly understood. Here, we found that Bmps was ubiquitously expressed in all the tested tissues during metamorphosis. In the current study, loss-of-function analysis of Bmps was performed by the binary transgenic CRISPR/cas9 system. Compared with the wild type, the developmental time of ∆Bmps animals were significantly delayed. In addition, ∆Bmps showed abnormal appendage including antenna, leg, wing and eye during pupal and adult stages. RNA-seq analysis indicated that apoptosis and proliferation related pathways were affected in ∆Bmps. Moreover, the Hippo pathway was affected by Bmps depletion in brain and wing disc. Our results suggest that PS is essential for maintaining the dynamic balance of apoptosis and proliferation during metamorphosis.
Topics: Animals; Bombyx; Insect Proteins; Larva; Metamorphosis, Biological; Presenilins; Pupa
PubMed: 34811799
DOI: 10.1002/arch.21855 -
Current Opinion in Cell Biology Oct 2001Presenilins are needed for proteolytic processing of transmembrane proteins of the Notch/Lin-12 family and for cleavage of the amyloid precursor protein. Accumulating... (Review)
Review
Presenilins are needed for proteolytic processing of transmembrane proteins of the Notch/Lin-12 family and for cleavage of the amyloid precursor protein. Accumulating evidence now strongly implicates Presenilin as the catalytic core of a multiprotein complex that executes an unusual intramembranous cleavage of its substrates. In the case of amyloid precursor protein, this cleavage contributes to the generation of small, toxic amyloid peptides that trigger the pathological development of Alzheimer's disease. In the Notch/Lin-12 pathway, Presenilin-mediated cleavage of the receptor is a crucial feature of ligand-induced receptor activation and signal transduction. In this pathway, the Presenilins perform a regulated cleavage event that follows additional processing steps during receptor maturation and ligand-induced ectodomain removal.
Topics: Amyloid beta-Protein Precursor; Animals; Caenorhabditis elegans Proteins; Helminth Proteins; Humans; Membrane Proteins; Models, Biological; Presenilin-1; Presenilin-2; Receptor, Notch1; Receptors, Cell Surface; Receptors, Notch; Signal Transduction; Transcription Factors
PubMed: 11544033
DOI: 10.1016/s0955-0674(00)00261-1 -
Human Mutation 1998The presenilins (PS-1 and PS-2) are 2 members of a novel family of genes encoding integral membrane proteins recently implicated in Alzheimer's disease (AD) pathology.... (Review)
Review
The presenilins (PS-1 and PS-2) are 2 members of a novel family of genes encoding integral membrane proteins recently implicated in Alzheimer's disease (AD) pathology. To date, 43 mutations have been identified in PS-1 and 2 in PS-2 that lead to familial presenile AD (onset before age 65 years). The normal and pathological functions of the PS proteins (ps-1 and ps-2) are unknown, but their high degree of homology predicts similar biological activities. Homologies with ps from other species suggest that they may play a role in intracellular protein sorting and trafficking, in intercellular cell signaling, or in cell death. Since to date only missense mutations and in-frame deletions were identified, it is believed that mutated ps act through either a gain of (dys-)function or a dominant negative effect. In vivo and in vitro studies have linked PS mutations to amyloid deposition, an early pathological event in AD brains.
Topics: Age of Onset; Alzheimer Disease; Humans; Membrane Proteins; Mutation; Presenilin-1; Presenilin-2
PubMed: 9521418
DOI: 10.1002/(SICI)1098-1004(1998)11:3<183::AID-HUMU1>3.0.CO;2-J -
Journal of Molecular Neuroscience : MN Nov 2016An imbalance in metal homeostasis is a prominent feature of Alzheimer's disease (AD). A wealth of evidence from independent studies over the past two and half decades... (Review)
Review
An imbalance in metal homeostasis is a prominent feature of Alzheimer's disease (AD). A wealth of evidence from independent studies over the past two and half decades has found changes to the distribution of brain iron, zinc, and copper in AD patients and animal models of the disease. Early research focused on the association of these metals with amyloid beta (Aβ), particularly extraneuronal Aβ plaque pathology. In contrast, there are numerous studies that have demonstrated a loss of iron-, zinc-, or copper-dependent cellular functions in AD animal and cell models, highlighting the importance of metal homeostasis in maintaining healthy brain function. Characterizing the molecular pathways that are impacted by iron, zinc, or copper will shed light on how these metals affect neuoroprotection, and conversely, neurodegeneration. Of particular interest is the role that the AD-associated presenilins have on protein trafficking and degradation, as metal homeostasis is dependent on the efficient trafficking and recycling of specific metal transporters. This review summarizes what is currently known about presenilin-dependent protein trafficking and the role of presenilin in protein turnover, particularly via the autophagy-lysosomal system.
Topics: Alzheimer Disease; Animals; Homeostasis; Humans; Metals; Presenilins; Protein Transport; Proteolysis
PubMed: 27558108
DOI: 10.1007/s12031-016-0826-4 -
Nature Reviews. Neurology Nov 2018Alzheimer disease (AD) is a debilitating dementia believed to result from the deposition of extracellular amyloid-β (Aβ)-containing plaques followed by the formation... (Review)
Review
Alzheimer disease (AD) is a debilitating dementia believed to result from the deposition of extracellular amyloid-β (Aβ)-containing plaques followed by the formation of neurofibrillary tangles. Familial AD typically results from mutations in the genes encoding amyloid precursor protein (APP), presenilin 1 or presenilin 2. Variations in triggering receptor expressed on myeloid cells 2 (TREM2), one of several genes for which expression is restricted to microglia in the brain, have now been shown to increase the risk of developing late-onset AD. Microglia have been shown to respond to Aβ accumulation and neurodegenerative lesions, progressively acquiring a unique transcriptional and functional signature and evolving into disease-associated microglia (DAM). DAM attenuate the progression of neurodegeneration in certain mouse models, but inappropriate DAM activation accelerates neurodegenerative disease in other models. TREM2 is essential for maintaining microglial metabolic fitness during stress events, enabling microglial progression to a fully mature DAM profile and ultimately sustaining the microglial response to Aβ-plaque-induced pathology. Here, we review the current data detailing the role of TREM2 in microglial biology and AD.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Humans; Membrane Glycoproteins; Microglia; Mutation; Presenilins; Receptors, Immunologic
PubMed: 30266932
DOI: 10.1038/s41582-018-0072-1