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Alzheimer's Research & Therapy Aug 2022In fewer than 1% of patients, AD is caused by autosomal dominant mutations in either the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP)...
BACKGROUND
In fewer than 1% of patients, AD is caused by autosomal dominant mutations in either the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes. The full extent of familial AD and frequency of these variants remains understudied in Latin American (LatAm) countries. Due to the rare nature of these variants, determining the pathogenicity of a novel variant in these genes can be challenging. Here, we use a systematic approach to assign the likelihood of pathogenicity in variants from densely affected families in Latin American populations.
METHODS
Clinical data was collected from LatAm families at risk for DIAD. Symptomatic family members were identified and assessed by local clinicians and referred for genetic counseling and testing. To determine the likelihood of pathogenicity among variants of unknown significance from LatAm populations, we report pedigree information, frequency in control populations, in silico predictions, and cell-based models of amyloid-beta ratios.
RESULTS
We identified five novel variants in the presenilin1 (PSEN1) gene from Brazilian and Mexican families. The mean age at onset in newly identified families was 43.5 years (range 36-54). PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, p.Ala275Thr, and p.Ile414Thr variants have not been reported in PubMed, ClinVar, and have not been reported in dominantly inherited AD (DIAD) families. We found that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr produce Aβ profiles consistent with known AD pathogenic mutations. PSEN1 p.Ile414Thr did not alter Aβ in a manner consistent with a known pathogenic mutation.
CONCLUSIONS
Our study provides further insights into the genetics of AD in LatAm. Based on our findings, including clinical presentation, imaging, genetic, segregations studies, and cell-based analysis, we propose that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr are likely pathogenic variants resulting in DIAD, whereas PSEN1 p.Ile414Thr is likely a risk factor. This report is a step forward to improving the inclusion/engagement of LatAm families in research. Family discovery is of great relevance for the region, as new initiatives are underway to extend clinical trials and observational studies to families living with DIAD.
Topics: Adult; Alzheimer Disease; Amyloid beta-Protein Precursor; Humans; Latin America; Middle Aged; Mutation; Presenilin-1
PubMed: 35932032
DOI: 10.1186/s13195-022-01052-1 -
The EMBO Journal Mar 2024Two phase-III clinical trials with anti-amyloid peptide antibodies have met their primary goal, i.e. slowing of Alzheimer's disease (AD) progression. However, antibody... (Review)
Review
Two phase-III clinical trials with anti-amyloid peptide antibodies have met their primary goal, i.e. slowing of Alzheimer's disease (AD) progression. However, antibody therapy may not be the optimal therapeutic modality for AD prevention, as we will discuss in the context of the earlier small molecules described as "γ-secretase modulators" (GSM). We review here the structure, function, and pathobiology of γ-secretases, with a focus on how mutations in presenilin genes result in early-onset AD. Significant progress has been made in generating compounds that act in a manner opposite to pathogenic presenilin mutations: they stabilize the proteinase-substrate complex, thereby increasing the processivity of substrate cleavage and altering the size spectrum of Aβ peptides produced. We propose the term "γ-secretase allosteric stabilizers" (GSAS) to distinguish these compounds from the rather heterogenous class of GSM. The GSAS represent, in theory, a precision medicine approach to the prevention of amyloid deposition, as they specifically target a discrete aspect in a complex cell biological signalling mechanism that initiates the pathological processes leading to Alzheimer's disease.
Topics: Humans; Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Precision Medicine; Presenilins; Presenilin-1; Amyloid beta-Protein Precursor
PubMed: 38396302
DOI: 10.1038/s44318-024-00057-w -
Molecular and Cellular Biology Sep 2020Neuronal ceroid lipofuscinosis (NCL) is one of the most prevalent neurodegenerative disorders of early life, Parkinson's disease (PD) is the most common... (Review)
Review
Neuronal ceroid lipofuscinosis (NCL) is one of the most prevalent neurodegenerative disorders of early life, Parkinson's disease (PD) is the most common neurodegenerative disorder of midlife, while Alzheimer's disease (AD) is the most common neurodegenerative disorder of late life. While they are phenotypically distinct, recent studies suggest that they share a biological pathway, retromer-dependent endosomal trafficking. A retromer is a multimodular protein assembly critical for sorting and trafficking cargo out of the endosome. As a lysosomal storage disease, all 13 of NCL's causative genes affect endolysosomal function, and at least four have been directly linked to retromer. PD has several known causative genes, with one directly linked to retromer and others causing endolysosomal dysfunction. AD has over 25 causative genes/risk factors, with several of them linked to retromer or endosomal trafficking dysfunction. In this article, we summarize the emerging evidence on the association of genes causing NCL with retromer function and endosomal trafficking, review the recent evidence linking NCL genes to AD, and discuss how NCL, AD, and PD converge on a shared molecular pathway. We also discuss this pathway's role in microglia and neurons, cell populations which are critical to proper brain homeostasis and whose dysfunction plays a key role in neurodegeneration.
Topics: Alzheimer Disease; Animals; Biological Transport; Endosomes; Humans; Neuronal Ceroid-Lipofuscinoses; Parkinson Disease; Presenilin-1
PubMed: 32690545
DOI: 10.1128/MCB.00262-20 -
Brain Research Bulletin Dec 2023Patients with chronic pain often have cognitive impairment; this is especially true in elderly patients with neurodegenerative diseases such as Alzheimer's disease (AD),...
Patients with chronic pain often have cognitive impairment; this is especially true in elderly patients with neurodegenerative diseases such as Alzheimer's disease (AD), but the mechanism underlying this association remains unclear. This was addressed in the present study by investigating the effect of chronic neuropathic pain on hippocampal neurogenesis and cognitive impairment using amyloid precursor protein/presenilin 1 (APP/PS1) double transgenic mice subjected to spared-nerve injury (SNI). The Von Frey test was performed to determine the mechanical threshold of mouse hind limbs after SNI. The Morris water maze test was used to evaluate spatial learning and memory. Doublecortin-positive (DCX), 5-bromo-2'-deoxyuridine (BrdU), BrdU/neuronal nuclei (NeuN), and C-C motif chemokine ligand 2 (CCL2) neurons in the dentate gyrus of the hippocampus were detected by immunohistochemistry and immunofluorescence analysis. CCL2 and C-C chemokine receptor type 2 (CCR2) protein levels in the mouse hippocampus were analyzed by western blotting. The results showed that APP/PS1 mice with chronic neuropathic pain induced by SNI had significant learning and memory impairment. This was accompanied by increased CCL2 and CCR2 expression and decreases in the number of DCX, BrdU, and BrdU/NeuN neurons. These results suggest that chronic neuropathic pain is associated with cognitive impairment, which may be caused by CCL2/CCR2 signaling-mediated inhibition of hippocampal neurogenesis. Thus, therapeutic strategies that alleviate neuropathic pain can potentially slow cognitive decline in patients with AD and other neurodegenerative diseases.
Topics: Aged; Animals; Mice; Alzheimer Disease; Amyloid beta-Protein Precursor; Bromodeoxyuridine; Chemokines; Chronic Pain; Cognitive Dysfunction; Disease Models, Animal; Hippocampus; Ligands; Mice, Transgenic; Neuralgia; Neurodegenerative Diseases; Neurogenesis; Presenilin-1; Receptors, Chemokine; Chemokine CCL2; Receptors, CCR2
PubMed: 37931808
DOI: 10.1016/j.brainresbull.2023.110801 -
Molecular Psychiatry Oct 2021Autosomal-dominant Alzheimer's disease (ADAD) may be associated with atypical amyloid beta deposits in the brain. In vivo amyloid imaging using C-Pittsburgh compound B...
Autosomal-dominant Alzheimer's disease (ADAD) may be associated with atypical amyloid beta deposits in the brain. In vivo amyloid imaging using C-Pittsburgh compound B (PiB) tracer has shown differences in binding between brains from ADAD and sporadic Alzheimer's disease (sAD) patients. To gain further insight into the various pathological characteristics of these genetic variants, we performed large frozen hemisphere autoradiography and brain homogenate binding assays with H-PiB, H-MK6240-H-THK5117, and H-deprenyl for detection of amyloid fibrils, tau depositions, and activated astrocytes, respectively, in two AβPParc mutation carriers, one PSEN1ΔE9 mutation carrier, and three sAD cases. The results were compared with Abeta 40, Abeta 42, AT8, and GFAP immunostaining, respectively, as well as with Congo red and Bielschowsky. PiB showed a very low binding in AβPParc. A high binding was observed in PSEN1ΔE9 and in sAD tissues but with different binding patterns. Comparable H-THK5117 and H-deprenyl brain homogenate binding was observed for AβPParc, PSEN1ΔE9, and sAD, respectively. Some differences were observed between H-MK6240 and H-THK5117 in ADAD. A positive correlation between H-deprenyl and H-THK5117 binding was observed in AβPParc, while no such correlation was found in PSEN1ΔE9 and sAD. Our study demonstrates differences in the properties of the amyloid plaques between two genetic variants of AD and sAD. Despite the lack of measurable amyloid fibrils by PiB in the AβPParc cases, high regional tau and astrocyte binding was observed. The lack of correlation between H-deprenyl and H-THK5117 binding in PSEN1ΔE9 and sAD in contrast of the positive correlation observed in the AβPParc cases suggest differences in the pathological cascade between variants of AD that warrant further exploration in vivo.
Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Aniline Compounds; Astrocytes; Brain; Humans; Plaque, Amyloid; Positron-Emission Tomography; Presenilin-1; tau Proteins
PubMed: 32581318
DOI: 10.1038/s41380-020-0817-2 -
Cells Jan 2021Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder in which learning, memory and cognitive functions decline progressively. Familial...
Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder in which learning, memory and cognitive functions decline progressively. Familial forms of AD (FAD) are caused by mutations in amyloid precursor protein (), presenilin 1 () and presenilin 2 () genes. Presenilin 1 (PS1) and its homologue, presenilin 2 (PS2), represent, alternatively, the catalytic core of the γ-secretase complex that, by cleaving APP, produces neurotoxic amyloid beta (Aβ) peptides responsible for one of the histopathological hallmarks in AD brains, the amyloid plaques. Recently, FAD mutations have been associated with a loss-of-function phenotype. To investigate whether this finding can also be extended to FAD mutations, we studied two processes known to be modulated by PS2 and altered by FAD mutations: Ca signaling and mitochondrial function. By exploiting neurons derived from a knock-out (PS2-/-) mouse model, we found that, upon IP-generating stimulation, cytosolic Ca handling is not altered, compared to wild-type cells, while mitochondrial Ca uptake is strongly compromised. Accordingly, PS2-/- neurons show a marked reduction in endoplasmic reticulum-mitochondria apposition and a slight alteration in mitochondrial respiration, whereas mitochondrial membrane potential, and organelle morphology and number appear unchanged. Thus, although some alterations in mitochondrial function appear to be shared between PS2-/- and FAD-PS2-expressing neurons, the mechanisms leading to these defects are quite distinct between the two models. Taken together, our data appear to be difficult to reconcile with the proposal that FAD-PS2 mutants are loss-of-function, whereas the concept that PS2 plays a key role in sustaining mitochondrial function is here confirmed.
Topics: Adenosine Triphosphate; Alzheimer Disease; Animals; Calcium Signaling; Cell Respiration; Citric Acid Cycle; Cytosol; Endoplasmic Reticulum; Glycolysis; Membrane Potential, Mitochondrial; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Neurons; Oxidative Phosphorylation; Phenotype; Presenilin-2; Mice
PubMed: 33494218
DOI: 10.3390/cells10020204 -
Brain Research Bulletin Aug 2023Synapse loss is a major contributor to cognitive dysfunction in Alzheimer's disease (AD). Impairments in the expression and/or glutamate uptake activity of glia...
Ceftriaxone ameliorates hippocampal synapse loss by inhibiting microglial/macrophages activation in glial glutamate transporter-1 dependent manner in the APP/PS1 mouse model of Alzheimer's disease.
Synapse loss is a major contributor to cognitive dysfunction in Alzheimer's disease (AD). Impairments in the expression and/or glutamate uptake activity of glia glutamate transporter-1 (GLT-1) contribute to synapse loss in AD. Hence, targeting the restoration of GLT-1 activity may have potential for alleviating synapse loss in AD. Ceftriaxone (Cef) can upregulate the expression and glutamate uptake activity of GLT-1 in many disease models, including those for AD. The present study investigated the effects of Cef on synapse loss and the role of GLT-1 using APP/PS1 transgenic and GLT-1 knockdown APP/PS1 AD mice. Furthermore, the involvement of microglia in the process was investigated due to its important role in synapse loss in AD. We found that Cef treatment significantly ameliorated synapse loss and dendritic degeneration in APP/PS1 AD mice, evidenced by an increased dendritic spine density, decreased dendritic beading density, and upregulated levels of postsynaptic density protein 95 (PSD95) and synaptophysin. The effects of Cef were suppressed by GLT-1 knockdown in GLT-1/APP/PS1 AD mice. Simultaneously, Cef treatment inhibited ionized calcium binding adapter molecule 1 (Iba1) expression, decreased the proportion of CD11bCD45 cells, declined interleukin-6 (IL-6) content, and reduced the co-expression of Iba1 with PSD95 or synaptophysin in APP/PS1 AD mice. In conclusion, Cef treatment ameliorated synapse loss and dendritic degeneration in APP/PS1 AD mice in a GLT-1-dependent manner, and the inhibitory effect of Cef on the activation of microglia/macrophages and their phagocytosis for synaptic elements contributed to the mechanism.
Topics: Mice; Animals; Alzheimer Disease; Ceftriaxone; Microglia; Synaptophysin; Mice, Transgenic; Hippocampus; Glutamic Acid; Synapses; Macrophages; Disks Large Homolog 4 Protein; Amino Acid Transport System X-AG; Disease Models, Animal; Amyloid beta-Protein Precursor; Presenilin-1; Amyloid beta-Peptides
PubMed: 37301482
DOI: 10.1016/j.brainresbull.2023.110683 -
Molecular Psychiatry Oct 2021Amyloid-β peptide (Aβ) accumulation in the brain is a hallmark of Alzheimer's Disease. An important mechanism of Aβ clearance in the brain is uptake and degradation...
Amyloid-β peptide (Aβ) accumulation in the brain is a hallmark of Alzheimer's Disease. An important mechanism of Aβ clearance in the brain is uptake and degradation by microglia. Presenilin 1 (PS1) is the catalytic subunit of γ-secretase, an enzyme complex responsible for the maturation of multiple substrates, such as Aβ. Although PS1 has been extensively studied in neurons, the role of PS1 in microglia is incompletely understood. Here we report that microglia containing phospho-deficient mutant PS1 display a slower kinetic response to micro injury in the brain in vivo and the inability to degrade Aβ oligomers due to a phagolysosome dysfunction. An Alzheimer's mouse model containing phospho-deficient PS1 show severe Aβ accumulation in microglia as well as the postsynaptic protein PSD95. Our results demonstrate a novel mechanism by which PS1 modulates microglial function and contributes to Alzheimer's -associated phenotypes.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Mice; Microglia; Phosphorylation; Presenilin-1
PubMed: 32792660
DOI: 10.1038/s41380-020-0856-8 -
The Journal of Neuroscience : the... May 2021Tau aggregation within neurons is a critical feature of Alzheimer's disease (AD) and related tauopathies. It is believed that soluble pathologic tau species seed the...
Tau aggregation within neurons is a critical feature of Alzheimer's disease (AD) and related tauopathies. It is believed that soluble pathologic tau species seed the formation of tau aggregates in a prion-like manner and propagate through connected neurons during the progression of disease. Both soluble and aggregated forms of tau are thought to have neurotoxic properties. In addition, different strains of misfolded tau may cause differential neurotoxicity. In this work, we present an accelerated human neuronal model of tau-induced neurotoxicity that incorporates both soluble tau species and tau aggregation. Using patient-derived induced pluripotent stem cell (iPSC) neurons expressing a tau aggregation biosensor, we develop a cell culture system that allows continuous assessment of both induced tau aggregation and neuronal viability at single-cell resolution for periods of >1 week. We show that exogenous tau "seed" uptake, as measured by tau repeat domain (TauRD) reporter aggregation, increases the risk for subsequent neuronal death These results are the first to directly visualize neuronal TauRD aggregation and subsequent cell death in single human iPSC neurons. Specific morphologic strains or patterns of TauRD aggregation are then identified and associated with differing neurotoxicity. Furthermore, we demonstrate that familial AD iPSC neurons expressing the PSEN1 L435F mutation exhibit accelerated TauRD aggregation kinetics and a tau strain propagation bias when compared with control iPSC neurons. Neuronal intracellular aggregation of the microtubule binding protein tau occurs in Alzheimer's disease and related neurodegenerative tauopathies. Tau aggregates are believed to spread from neuron to neuron via prion-like misfolded tau seeds. Our work develops a human neuronal live-imaging system to visualize seeded tau aggregation and tau-induced neurotoxicity within single neurons. Using an aggregation-sensing tau reporter, we find that neuronal uptake and propagation of tau seeds reduces subsequent survival. In addition, human induced pluripotent stem cell (iPSC) neurons carrying an Alzheimer's disease-causing mutation in presenilin-1 undergo tau seeding more rapidly than control iPSC neurons. However, they do not show subsequent differences in neuronal survival. Finally, specific morphologies of tau aggregates are associated with increased neurotoxicity.
Topics: Aged, 80 and over; Alzheimer Disease; Animals; Cell Survival; Cells, Cultured; Female; Humans; Induced Pluripotent Stem Cells; Male; Mice; Middle Aged; Neurotoxicity Syndromes; Presenilin-1; Tauopathies; tau Proteins
PubMed: 33893219
DOI: 10.1523/JNEUROSCI.2590-20.2021 -
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