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Nutrients Oct 2023The deterioration of brain glucose metabolism predates the clinical onset of Alzheimer's disease (AD). Medium-chain triglycerides (MCTs) and docosahexaenoic acid (DHA)...
Supplementation of Medium-Chain Triglycerides Combined with Docosahexaenoic Acid Inhibits Amyloid Beta Protein Deposition by Improving Brain Glucose Metabolism in APP/PS1 Mice.
The deterioration of brain glucose metabolism predates the clinical onset of Alzheimer's disease (AD). Medium-chain triglycerides (MCTs) and docosahexaenoic acid (DHA) positively improve brain glucose metabolism and decrease the expression of AD-related proteins. However, the effects of the combined intervention are unclear. The present study explored the effects of the supplementation of MCTs combined with DHA in improving brain glucose metabolism and decreasing AD-related protein expression levels in APP/PS1 mice. The mice were assigned into four dietary treatment groups: the control group, MCTs group, DHA group, and MCTs + DHA group. The corresponding diet of the respective groups was fed to mice from the age of 3 to 11 months. The results showed that the supplementation of MCTs combined with DHA could increase serum octanoic acid (C8:0), decanoic acid (C10:0), DHA, and β-hydroxybutyrate (β-HB) levels; improve glucose metabolism; and reduce nerve cell apoptosis in the brain. Moreover, it also aided with decreasing the expression levels of amyloid beta protein (Aβ), amyloid precursor protein (APP), β-site APP cleaving enzyme-1 (BACE1), and presenilin-1 (PS1) in the brain. Furthermore, the supplementation of MCTs + DHA was significantly more beneficial than that of MCTs or DHA alone. In conclusion, the supplementation of MCTs combined with DHA could improve energy metabolism in the brain of APP/PS1 mice, thus decreasing nerve cell apoptosis and inhibiting the expression of Aβ.
Topics: Mice; Animals; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Docosahexaenoic Acids; Presenilin-1; Mice, Transgenic; Aspartic Acid Endopeptidases; Disease Models, Animal; Alzheimer Disease; Brain; Dietary Supplements; Triglycerides
PubMed: 37836528
DOI: 10.3390/nu15194244 -
Autophagy May 2024Tripartite motif (TRIM) proteins are a large family of E3 ubiquitin ligases implicated in antiviral defense systems, tumorigenesis, and protein quality control. TRIM...
Tripartite motif (TRIM) proteins are a large family of E3 ubiquitin ligases implicated in antiviral defense systems, tumorigenesis, and protein quality control. TRIM proteins contribute to protein quality control by regulating the ubiquitin-proteasome system, endoplasmic reticulum-associated degradation, and macroautophagy/autophagy. However, the detailed mechanisms through which various TRIM proteins regulate downstream events have not yet been fully elucidated. Herein, we identified a novel function of TRIM22 in the regulation of autophagy. TRIM22 promotes autophagosome-lysosome fusion by mediating the association of GABARAP family proteins with PLEKHM1, thereby inducing the autophagic clearance of protein aggregates, independent of its E3 ubiquitin ligase activity. Furthermore, a TRIM22 variant associated with early-onset familial Alzheimer disease interferes with autophagosome-lysosome fusion and autophagic clearance. These findings suggest TRIM22 as a critical autophagic regulator that orchestrates autophagosome-lysosome fusion by scaffolding autophagy-related proteins, thus representing a potential therapeutic target in neurodegenerative diseases. AD: Alzheimer disease; ADAOO: AD age of onset; AICD: APP intracellular domain; APP: amyloid beta precursor protein; BSA: bovine serum albumin; cDNAs: complementary DNAs; CQ: chloroquine; CTF: carboxyl-terminal fragment; EBSS: Earle's balanced salt solution; GABARAP: GABA type A receptor-associated protein; GST: glutathione S-transferase; HA: hemagglutinin; HOPS: homotypic fusion and protein sorting; IFN: interferon; IL1A/IL-1α: interleukin 1 alpha; KO: knockout; MTORC1: mechanistic target of rapamycin kinase complex 1; NFKBIA/IκBα: NFKB inhibitor alpha; NFE2L2/NRF2: NFE2 like bZIP transcription factor; PBS: phosphate-buffered saline; PI3K: class I phosphoinositide 3-kinase; PLA: proximity ligation assay; PLEKHM1: pleckstrin homology and RUN domain containing M1; PSEN1: presenilin 1; SEM: standard errors of the means; SNAREs: soluble N-ethylmaleimide-sensitive factor attachment protein receptors; SNCA: synuclein alpha; SNP: single nucleotide polymorphism; TBS: tris-buffered saline; TNF/TNF-α: tumor necrosis factor; TRIM: tripartite motif; ULK1: unc-51 like autophagy activating kinase 1; WT: wild-type.
Topics: Autophagosomes; Humans; Lysosomes; Autophagy; Tripartite Motif Proteins; Membrane Fusion; Adaptor Proteins, Signal Transducing; Microtubule-Associated Proteins; HEK293 Cells; Apoptosis Regulatory Proteins; Alzheimer Disease; Protein Binding; Animals; Autophagy-Related Proteins; Repressor Proteins; Minor Histocompatibility Antigens
PubMed: 38009729
DOI: 10.1080/15548627.2023.2287925 -
Genetics in Medicine : Official Journal... May 2024To assess the likely pathogenic/pathogenic (LP/P) variants rates in Mendelian dementia genes and the moderate-to-strong risk factors rates in patients with Alzheimer...
PURPOSE
To assess the likely pathogenic/pathogenic (LP/P) variants rates in Mendelian dementia genes and the moderate-to-strong risk factors rates in patients with Alzheimer disease (AD).
METHODS
We included 700 patients in a prospective study and performed exome sequencing. A panel of 28 Mendelian and 6 risk-factor genes was interpreted and returned to patients. We built a framework for risk variant interpretation and risk gradation and assessed the detection rates among early-onset AD (EOAD, age of onset (AOO) ≤65 years, n = 608) depending on AOO and pedigree structure and late-onset AD (66 < AOO < 75, n = 92).
RESULTS
Twenty-one patients carried a LP/P variant in a Mendelian gene (all with EOAD, 3.4%), 20 of 21 affected APP, PSEN1, or PSEN2. LP/P variant detection rates in EOAD ranged from 1.7% to 11.6% based on AOO and pedigree structure. Risk factors were found in 69.5% of the remaining 679 patients, including 83 (12.2%) being heterozygotes for rare risk variants, in decreasing order of frequency, in TREM2, ABCA7, ATP8B4, SORL1, and ABCA1, including 5 heterozygotes for multiple rare risk variants, suggesting non-monogenic inheritance, even in some autosomal-dominant-like pedigrees.
CONCLUSION
We suggest that genetic screening should be proposed to all EOAD patients and should no longer be prioritized based on pedigree structure.
Topics: Humans; Alzheimer Disease; Genetic Testing; Female; Male; Genetic Predisposition to Disease; Aged; Risk Factors; Prospective Studies; Exome Sequencing; Middle Aged; Presenilin-2; Presenilin-1; Pedigree; Age of Onset; Amyloid beta-Protein Precursor; Aged, 80 and over; Membrane Glycoproteins; Receptors, Immunologic
PubMed: 38281098
DOI: 10.1016/j.gim.2024.101082 -
The Journal of Biological Chemistry Jan 2024The γ-secretase complexes are intramembrane cleaving proteases involved in the generation of the Aβ peptides in Alzheimer's disease. The complex consists of four...
The γ-secretase complexes are intramembrane cleaving proteases involved in the generation of the Aβ peptides in Alzheimer's disease. The complex consists of four subunits, with Presenilin harboring the catalytic site. Here, we study the role of the smallest subunit, PSENEN or Presenilin enhancer 2, encoded by the gene Psenen, in vivo and in vitro. We find a profound Notch deficiency phenotype in Psenen embryos confirming the essential role of PSENEN in the γ-secretase complex. We used Psenen fibroblasts to explore the structure-function of PSENEN by the scanning cysteine accessibility method. Glycine 22 and proline 27, which border the membrane domains 1 and 2 of PSENEN, are involved in complex formation and stabilization of γ-secretase. The hairpin structured hydrophobic membrane domains 1 and 2 are exposed to a water-containing cavity in the complex, while transmembrane domain 3 is not water exposed. We finally demonstrate the essential role of PSENEN for the cleavage activity of the complex. PSENEN is more than a structural component of the γ-secretase complex and might contribute to the catalytic mechanism of the enzyme.
Topics: Animals; Female; Male; Mice; Amyloid Precursor Protein Secretases; Cell Membrane; Cells, Cultured; Membrane Proteins; Mice, Inbred C57BL; Presenilin-1; Protein Structure, Tertiary
PubMed: 38072061
DOI: 10.1016/j.jbc.2023.105533 -
International Journal of Molecular... Oct 2023Alzheimer's disease (AD), the most prevalent form of dementia, is a neurodegenerative disorder characterized by different pathological symptomatology, including...
Alzheimer's disease (AD), the most prevalent form of dementia, is a neurodegenerative disorder characterized by different pathological symptomatology, including disrupted circadian rhythm. The regulation of circadian rhythm depends on the light information that is projected from the retina to the suprachiasmatic nucleus in the hypothalamus. Studies of AD patients and AD transgenic mice have revealed AD retinal pathology, including amyloid-β (Aβ) accumulation that can directly interfere with the regulation of the circadian cycle. Although the cause of AD pathology is poorly understood, one of the main risk factors for AD is female gender. Here, we found that female APP/PS1 mice at 6- and 12-months old display severe circadian rhythm disturbances and retinal pathological hallmarks, including Aβ deposits in retinal layers. Since brain Aβ transport is facilitated by aquaporin (AQP)4, the expression of AQPs were also explored in APP/PS1 retina to investigate a potential correlation between retinal Aβ deposits and AQPs expression. Important reductions in AQP1, AQP4, and AQP5 were detected in the retinal tissue of these transgenic mice, mainly at 6-months of age. Taken together, our findings suggest that abnormal transport of Aβ, mediated by impaired AQPs expression, contributes to the retinal degeneration in the early stages of AD.
Topics: Mice; Humans; Female; Animals; Infant; Amyloid beta-Protein Precursor; Alzheimer Disease; Amyloid beta-Peptides; Mice, Transgenic; Retina; Aquaporin 4; Gene Expression; Disease Models, Animal; Presenilin-1; Plaque, Amyloid
PubMed: 37958666
DOI: 10.3390/ijms242115679 -
International Journal of Molecular... Feb 2024Alzheimer's disease (AD), the leading cause of dementia, presents a significant global health challenge with no known cure to date. Central to our understanding of AD... (Review)
Review
Alzheimer's disease (AD), the leading cause of dementia, presents a significant global health challenge with no known cure to date. Central to our understanding of AD pathogenesis is the β-amyloid cascade hypothesis, which underlies drug research and discovery efforts. Despite extensive studies, no animal models of AD have completely validated this hypothesis. Effective AD models are essential for accurately replicating key pathological features of the disease, notably the formation of β-amyloid plaques and neurofibrillary tangles. These pathological markers are primarily driven by mutations in the amyloid precursor protein (APP) and presenilin 1 (PS1) genes in familial AD (FAD) and by tau protein mutations for the tangle pathology. Transgenic mice models have been instrumental in AD research, heavily relying on the overexpression of mutated APP genes to simulate disease conditions. However, these models do not entirely replicate the human condition of AD. This review aims to provide a comprehensive evaluation of the historical and ongoing research efforts in AD, particularly through the use of transgenic mice models. It is focused on the benefits gathered from these transgenic mice models in understanding β-amyloid toxicity and the broader biological underpinnings of AD. Additionally, the review critically assesses the application of these models in the preclinical testing of new therapeutic interventions, highlighting the gap between animal models and human clinical realities. This analysis underscores the need for refinement in AD research methodologies to bridge this gap and enhance the translational value of preclinical studies.
Topics: Mice; Animals; Humans; Alzheimer Disease; Mice, Transgenic; Disease Models, Animal; tau Proteins; Amyloid beta-Protein Precursor; Amyloid beta-Peptides; Presenilin-1; Plaque, Amyloid
PubMed: 38474051
DOI: 10.3390/ijms25052805 -
Alzheimer's & Dementia : the Journal of... Apr 2024Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1...
INTRODUCTION
Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages.
METHODS
Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition.
RESULTS
Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures.
DISCUSSION
We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials.
HIGHLIGHTS
Mutation position influences Aβ burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aβ burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage.
Topics: Humans; Alzheimer Disease; Amyloidosis; Cerebral Small Vessel Diseases; Diffusion Tensor Imaging; Magnetic Resonance Imaging; Mutation; Presenilin-1
PubMed: 38380882
DOI: 10.1002/alz.13729 -
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 -
Frontiers in Molecular Neuroscience 2024A patient with the E280A mutation and homozygous for Christchurch () displayed extreme resistance to Alzheimer's disease (AD) cognitive decline and tauopathy, despite...
A patient with the E280A mutation and homozygous for Christchurch () displayed extreme resistance to Alzheimer's disease (AD) cognitive decline and tauopathy, despite having a high amyloid burden. To further investigate the differences in biological processes attributed to , we generated induced pluripotent stem (iPS) cell-derived cerebral organoids from this resistant case and a non-protected control, using CRISPR/Cas9 gene editing to modulate expression. In the cerebral organoids, we observed a protective pattern from early tau phosphorylation. ScRNA sequencing revealed regulation of Cadherin and Wnt signaling pathways by , with immunostaining indicating elevated β-catenin protein levels. Further reporter assays unexpectedly demonstrated that ApoE3Ch functions as a Wnt3a signaling enhancer. This work uncovered a neomorphic molecular mechanism of protection of ApoE3 Christchurch, which may serve as the foundation for the future development of protected case-inspired therapeutics targeting AD and tauopathies.
PubMed: 38571814
DOI: 10.3389/fnmol.2024.1373568 -
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