Simvastatin, Its Antimicrobial Activity and Its Prevention of Alzheimer’s Disease DOI Creative Commons
Sudip Dhakal, Ian Macreadie

Microorganisms, Год журнала: 2024, Номер 12(6), С. 1133 - 1133

Опубликована: Июнь 1, 2024

Simvastatin, a blockbuster drug for treating hypercholesterolemia, has multifactorial benefits as an antimicrobial agent and plays preventative role in reducing the incidence of Alzheimer’s Disease (AD). Although most beneficial effects simvastatin have been attributed to its ability reduce cholesterol levels, recent scientific studies suggested that are largely due pleiotropic targeting other pathways, e.g., by inhibiting protein lipidation. There certain can be predicted from inhibition mevalonate pathway; however, some proteostasis lead reduced levels amyloid beta, key contributor AD. This review discusses use anti-AD drug.

Язык: Английский

PICALM and Alzheimer’s Disease: An Update and Perspectives DOI Creative Commons
Kunié Ando, Siranjeevi Nagaraj, Fahri Küçükali

и другие.

Cells, Год журнала: 2022, Номер 11(24), С. 3994 - 3994

Опубликована: Дек. 10, 2022

Genome-wide association studies (GWAS) have identified the PICALM (Phosphatidylinositol binding clathrin-assembly protein) gene as most significant genetic susceptibility locus after APOE and BIN1. is a clathrin-adaptor protein that plays critical role in clathrin-mediated endocytosis autophagy. Since effects of variants AD-susceptibility loci been confirmed by independent several distinct cohorts, there has number vitro vivo attempting to elucidate underlying mechanism which modulates AD risk. While differential modulation APP processing Aβ transcytosis reported, tau pathology progression also evidenced Alzheimer’s disease models. In this review, we summarize current knowledge about PICALM, its physiological functions, variants, post-translational modifications relevance pathogenesis.

Язык: Английский

Процитировано

51
Cytosolic antibody receptor TRIM21 is required for effective tau immunotherapy in mouse models DOI
Aamir S. Mukadam, Lauren V. C. Miller, Annabel E. Smith

и другие.

Science, Год журнала: 2023, Номер 379(6639), С. 1336 - 1341

Опубликована: Март 31, 2023

Aggregates of the protein tau are proposed to drive pathogenesis in neurodegenerative diseases. Tau can be targeted by using passively transferred antibodies (Abs), but mechanisms Ab protection incompletely understood. In this work, we used a variety cell and animal model systems showed that cytosolic receptor E3 ligase TRIM21 (T21) could play role against pathology. Tau-Ab complexes were internalized cytosol neurons, which enabled T21 engagement seeded aggregation. Ab-mediated pathology was lost mice lacked T21. Thus, compartment provides site immunotherapeutic protection, may help design Ab-based therapies disease.

Язык: Английский

Процитировано

39
Perforin-2 is a pore-forming effector of endocytic escape in cross-presenting dendritic cells DOI
Pablo Rodríguez-Silvestre,

Marco Laub,

Patrycja A. Krawczyk

и другие.

Science, Год журнала: 2023, Номер 380(6651), С. 1258 - 1265

Опубликована: Июнь 22, 2023

During initiation of antiviral and antitumor T cell–mediated immune responses, dendritic cells (DCs) cross-present exogenous antigens on major histocompatibility complex (MHC) class I molecules. Cross-presentation relies the unusual “leakiness” endocytic compartments in DCs, whereby internalized proteins escape into cytosol for proteasome-mediated generation MHC I–binding peptides. Given that type 1 conventional DCs excel at cross-presentation, we searched cell type–specific effectors escape. We devised an assay suitable genetic screening identified a pore-forming protein, perforin-2 ( Mpeg1 ), as dedicated effector exclusive to cross-presenting cells. Perforin-2 was recruited antigen-containing compartments, where it underwent maturation, releasing its domain. −/− mice failed efficiently prime CD8 + cell-associated antigens, revealing important role cytosolic entry during cross-presentation.

Язык: Английский

Процитировано

33
Cholesterol Metabolism in Aging and Age-Related Disorders DOI Creative Commons
Gesine Saher

Annual Review of Neuroscience, Год журнала: 2023, Номер 46(1), С. 59 - 78

Опубликована: Июль 10, 2023

All mammalian cell membranes contain cholesterol to maintain membrane integrity. The transport of this hydrophobic lipid is mediated by lipoproteins. Cholesterol especially enriched in the brain, particularly synaptic and myelin membranes. Aging involves changes sterol metabolism peripheral organs also brain. Some those alterations have potential promote or counteract development neurodegenerative diseases during aging. Here, we summarize current knowledge general principles humans mice, most widely used model organism biomedical research. We discuss that occur aged brain highlight recent developments type-specific fast-growing research field aging age-related diseases, focusing on Alzheimer's disease. propose handling interplay between types critically influence disease processes.

Язык: Английский

Процитировано

33
The Niemann-Pick type diseases – A synopsis of inborn errors in sphingolipid and cholesterol metabolism DOI Creative Commons
Frank W. Pfrieger

Progress in Lipid Research, Год журнала: 2023, Номер 90, С. 101225 - 101225

Опубликована: Март 31, 2023

Disturbances of lipid homeostasis in cells provoke human diseases. The elucidation the underlying mechanisms and development efficient therapies represent formidable challenges for biomedical research. Exemplary cases are two rare, autosomal recessive, ultimately fatal lysosomal diseases historically named "Niemann-Pick" honoring physicians, whose pioneering observations led to their discovery. Acid sphingomyelinase deficiency (ASMD) Niemann-Pick type C disease (NPCD) caused by specific variants sphingomyelin phosphodiesterase 1 (SMPD1) NPC intracellular cholesterol transporter (NPC1) or 2 (NPC2) genes that perturb key membrane components, cholesterol, respectively. Patients with severe forms these present visceral neurologic symptoms succumb premature death. This synopsis traces tortuous discovery diseases, highlights important advances respect genetic culprits cellular mechanisms, exposes efforts improve diagnosis explore new therapeutic approaches.

Язык: Английский

Процитировано

28
ER‐mitochondria contacts and cholesterol metabolism are disrupted by disease‐associated tau protein DOI Creative Commons
Leonora Szabo, Nadia Cummins, Paolo Paganetti

и другие.

EMBO Reports, Год журнала: 2023, Номер 24(8)

Опубликована: Июль 4, 2023

Abstract Abnormal tau protein impairs mitochondrial function, including transport, dynamics, and bioenergetics. Mitochondria interact with the endoplasmic reticulum (ER) via mitochondria‐associated ER membranes (MAMs), which coordinate modulate many cellular functions, cholesterol metabolism. Here, we show that abnormal loosens association between mitochondria in vivo vitro . Especially, ER‐mitochondria interactions vesicle‐associated membrane protein‐associated (VAPB)—protein tyrosine phosphatase‐interacting 51 (PTPIP51) are decreased presence of tau. Disruption MAMs cells alters levels pregnenolone, indicating conversion into pregnenolone is impaired. Opposite effects observed absence Besides, targeted metabolomics reveals overall alterations cholesterol‐related metabolites by The inhibition GSK3β decreases hyperphosphorylation increases VAPB–PTPIP51 interactions, restoring levels. This study first to highlight a link tau‐induced impairments interaction

Язык: Английский

Процитировано

24
Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy DOI Creative Commons
Danira Toral-Ríos, Justin M. Long, Jason D. Ulrich

и другие.

The Journal of Experimental Medicine, Год журнала: 2024, Номер 221(4)

Опубликована: Март 1, 2024

Alzheimer’s disease (AD) is characterized by amyloid plaques and neurofibrillary tangles, in addition to neuroinflammation changes brain lipid metabolism. 25-Hydroxycholesterol (25-HC), a known modulator of both inflammation metabolism, produced cholesterol 25-hydroxylase encoded Ch25h expressed as “disease-associated microglia” signature gene. However, whether influences tau-mediated neurodegeneration unknown. Here, we show that the absence resultant reduction 25-HC, there strikingly reduced age-dependent hippocampus entorhinal/piriform cortex PS19 mice, which express P301S mutant human tau transgene. Transcriptomic analyses bulk hippocampal tissue single nuclei revealed deficiency mice strongly suppressed proinflammatory signaling microglia. Our results suggest key role for Ch25h/25-HC potentiating promote neurodegeneration. may represent novel therapeutic target primary tauopathies, AD, other neuroinflammatory diseases.

Язык: Английский

Процитировано

12
Aggregate-selective removal of pathological tau by clustering-activated degraders DOI
Jonathan Benn, Shi Cheng, Sophie Keeling

и другие.

Science, Год журнала: 2024, Номер 385(6712), С. 1009 - 1016

Опубликована: Авг. 29, 2024

Selective degradation of pathological protein aggregates while sparing monomeric forms is major therapeutic interest. The E3 ligase tripartite motif–containing 21 (TRIM21) degrades antibody-bound proteins in an assembly state–specific manner due to the requirement TRIM21 RING domain clustering for activation, yet effective targeting intracellular assemblies remains challenging. Here, we fused a target-specific nanobody create intracellularly expressed constructs capable selectively degrading assembled proteins. We evaluated this approach against green fluorescent protein–tagged histone 2B (H2B-GFP) and tau, that undergoes aggregation Alzheimer’s other neurodegenerative diseases. RING-nanobody degraders prevented or reversed tau culture vivo, with minimal impact on tau. This may have potential many disorders driven by aggregation.

Язык: Английский

Процитировано

10
Gene networks and systems biology in Alzheimer's disease: Insights from multi‐omics approaches DOI Creative Commons
Negin Rahimzadeh, Shushrruth Sai Srinivasan, Jing Zhang

и другие.

Alzheimer s & Dementia, Год журнала: 2024, Номер 20(5), С. 3587 - 3605

Опубликована: Март 27, 2024

Despite numerous studies in the field of dementia and Alzheimer's disease (AD), a comprehensive understanding this devastating remains elusive. Bulk transcriptomics have provided insights into underlying genetic factors at high level. Subsequent technological advancements focused on single-cell omics, encompassing techniques such as RNA sequencing epigenomics, enabling capture transcripts chromatin states single cell or nucleus resolution. Furthermore, emergence spatial omics has allowed study gene responses vicinity amyloid beta plaques across various brain regions. With vast amount data generated, utilizing regulatory networks to comprehensively become essential. This review delves some employed AD, explores discoveries made using these techniques, provides future field.

Язык: Английский

Процитировано

9
Cholesterol imbalance and neurotransmission defects in neurodegeneration DOI Creative Commons
Kyung Chul Shin,

Houda Yasmine Ali Moussa,

Yongsoo Park

и другие.

Experimental & Molecular Medicine, Год журнала: 2024, Номер 56(8), С. 1685 - 1690

Опубликована: Авг. 1, 2024

The brain contains the highest concentration of cholesterol in human body, which emphasizes importance physiology. Cholesterol is involved neurogenesis and synaptogenesis, age-related reductions levels can lead to synaptic loss impaired plasticity, potentially contribute neurodegeneration. maintenance homeostasis neuronal plasma membrane essential for normal function, imbalances distribution are associated with various neurodegenerative disorders, including Alzheimer's disease, Parkinson's Huntington's disease. This review aims explore molecular pathological mechanisms by imbalance neurotransmission defects neurodegeneration, focusing on four key mechanisms: (1) dysfunction, (2) alterations structure protein clustering, (3) oligomers amyloid beta (Aβ) protein, (4) α-synuclein aggregation.

Язык: Английский

Процитировано

9