A novel apoE-mimetic increases brain apoE levels, reduces Aβ pathology and improves memory when treated before onset of pathology in male mice that express APOE3

Alzheimer s Research & Therapy, Год журнала: 2023, Номер 15(1)

Опубликована: Дек. 15, 2023

Abstract Background Alzheimer’s disease (AD) is characterized by cognitive dysfunction and amyloid plaques composed of the amyloid-beta peptide (Aβ). APOE greatest genetic risk for AD with APOE4 increasing up to ~ 15-fold compared APOE3. Evidence suggests that levels lipidation apoE protein could regulate progression. In glia, lipidated via cholesterol efflux from intracellular pools, primarily ATP-binding cassette transporter A1 (ABCA1). Therefore, ABCA1 activity suggested be a therapeutic approach AD. CS-6253 (CS) novel mimetic was developed bind stabilize maintain its localization into plasma membrane therefore promoting efflux. The goal this study determine whether CS modulate lipidation, Aβ pathology, behavior in model expresses human overproduce Aβ. Methods vitro, APOE3 -glia or were treated CS. vivo, male female, E3FAD (5xFAD +/− / +/+ ) E4FAD mice intraperitoneal injection at early (from 4 8 months age) late ages 10 age). ApoE levels, and, measured western blot ELISA. assessed histochemistry Learning memory tested Morris Water Maze synaptic proteins Western blot. Results treatment increased primary glial cultures. young mice, soluble lipid-associated apoE, reduced oAβ insoluble as well deposition, improved levels. did not induce any benefits female groups when started later ages. Conclusions pathology only E3FAD, cohort least pathology. degree overproduction may impact ability targeting an effective therapeutic. This ABCA1-stabilizing works best conditions modest

Язык: Английский

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Altered amyloid-β structure markedly reduces gliosis in the brain of mice harboring the Uppsala APP deletion

Acta Neuropathologica Communications, Год журнала: 2024, Номер 12(1)

Опубликована: Фев. 5, 2024

Deposition of amyloid beta (Aβ) into plaques is a major hallmark Alzheimer's disease (AD). Different precursor protein (APP) mutations cause early-onset AD by altering the production or aggregation properties Aβ. We recently identified Uppsala APP mutation (APPUpp), which causes Aβ pathology triple mechanism: increased β-secretase and altered α-secretase cleavage, leading to formation unique conformer that rapidly aggregates deposits in brain. The aim this study was further explore effects APPUpp transgenic mouse model (tg-UppSwe), expressing human with together APPSwe mutation. studied tg-UppSwe brains at different ages, using ELISA immunohistochemistry. In vivo PET imaging three radioligands conducted aged mice two other models; tg-ArcSwe tg-Swe. Finally, glial responses were cell culture models brain tissue, Tg-UppSwe displayed cleavage suppressed resulting AβUpp42 dominated diffuse plaque appearing from age 5-6 months. γ-secretase not affected. Contrary tg-Swe mice, [11C]PiB-PET negative. Antibody-based 3D6 ligand visualized all models, whereas protofibril selective mAb158 did give any signals mice. Moreover, unlike very faint response pathology. thus recapitulates several pathological features carriers. presumed structural found affect their interaction anti-Aβ antibodies profoundly modify Aβ-mediated response, may be important aspects consider for development therapies.

Язык: Английский

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Potential Mechanisms of Tunneling Nanotube Formation and Their Role in Pathology Spread in Alzheimer’s Disease and Other Proteinopathies

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(19), С. 10797 - 10797

Опубликована: Окт. 8, 2024

Alzheimer's disease (AD) is the most common type of dementia worldwide. The etiopathogenesis this remains unknown. Currently, several hypotheses attempt to explain its cause, with well-studied being cholinergic, beta-amyloid (Aβ), and Tau hypotheses. Lately, there has been increasing interest in role immunological factors other proteins such as alpha-synuclein (α-syn) transactive response DNA-binding protein 43 kDa (TDP-43). Recent studies emphasize tunneling nanotubes (TNTs) spread pathological within brains AD patients. TNTs are small membrane protrusions composed F-actin that connect non-adjacent cells. Conditions pathogen infections, oxidative stress, inflammation, misfolded accumulation lead formation TNTs. These structures have shown transport Aβ, Tau, α-syn, TDP-43 between central nervous system (CNS) cells, confirmed by vitro studies. Besides their spreading pathology, may also protective functions. Neurons burdened α-syn can transfer aggregates glial cells receive healthy mitochondria, thereby reducing cellular stress associated accumulation. Current treatments focus on alleviating symptoms, clinical trials Aβ-lowering drugs proven ineffective. Therefore, intensifying research could bring scientists closer a better understanding development effective therapies.

Язык: Английский

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Altered Distribution of SNARE Proteins in Primary Neurons Exposed to Different Alpha-Synuclein Proteoforms

Cellular and Molecular Neurobiology, Год журнала: 2023, Номер 43(6), С. 3023 - 3035

Опубликована: Май 2, 2023

Abstract Growing evidence indicates that the pathological alpha-synuclein (α-syn) aggregation in Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) starts at synapses. Physiologic α-syn is involved regulating neurotransmitter release by binding to SNARE complex protein VAMP-2 on synaptic vesicles. However, which way formation affected pathology remains unclear. In this study, primary cortical neurons were exposed either monomers or preformed fibrils (PFFs) for different time points effect distribution was analyzed a novel proximity ligation assay (PLA). Short-term exposure PFFs 24 h increased co-localization of syntaxin-1, but reduced SNAP-25 indicating direct added distribution. Long-term 7 d co-localization, although there only modest induction ser129 phosphorylated (pS129) α-syn. Similarly, extracellular vesicles collected from astrocytes treated influenced despite low levels pS129 being formed. Taken together, our results demonstrate proteoforms have potential alter proteins synapse. Graphical

Язык: Английский

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Tau processing and tau-mediated inflammation differ in human APOEε2 and APOEε4 astrocytes

iScience, Год журнала: 2024, Номер 27(11), С. 111163 - 111163

Опубликована: Окт. 11, 2024

Язык: Английский

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Early divergent modulation of NLRP2′s and NLRP3′s inflammasome sensors vs. AIM2′s one by signals from Aβ•Calcium-sensing receptor complexes in human astrocytes

Brain Research, Год журнала: 2024, Номер 1846, С. 149283 - 149283

Опубликована: Окт. 18, 2024

Язык: Английский

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