Alzheimer’s Amyloid Hypothesis and Antibody Therapy: Melting Glaciers?

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(7), С. 3892 - 3892

Опубликована: Март 31, 2024

The amyloid cascade hypothesis for Alzheimer's disease is still alive, although heavily challenged. Effective anti-amyloid immunotherapy would confirm the hypothesis' claim that protein amyloid-beta cause of disease. Two antibodies, aducanumab and lecanemab, have been approved by U.S. Food Drug Administration, while a third, donanemab, under review. main argument FDA approvals presumed therapy-induced removal cerebral deposits. Lecanemab donanemab are also thought to some statistical delay in determination cognitive decline. However, clinical efficacy less than with conventional treatment, selection amyloid-positive trial patients non-specific amyloid-PET imaging, uncertain amyloids trials cast doubt on this anti-Alzheimer's antibody therapy hence hypothesis, calling more thorough investigation negative impact type brain.

Язык: Английский

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Insulin resistance as the molecular link between diabetes and Alzheimer's disease

World Journal of Diabetes, Год журнала: 2024, Номер 15(7), С. 1430 - 1447

Опубликована: Июль 8, 2024

Diabetes mellitus (DM) and Alzheimer's disease (AD) are two major health concerns that have seen a rising prevalence worldwide. Recent studies indicated possible link between DM an increased risk of developing AD. Insulin, while primarily known for its role in regulating blood sugar, also plays vital protecting brain functions. Insulin resistance (IR), especially prevalent type 2 diabetes, is believed to play significant AD's development. When insulin signalling becomes dysfunctional, it can negatively affect various functions, making individuals more susceptible defining features, such as the buildup beta-amyloid plaques tau protein tangles. Emerging research suggests addressing insulin-related issues might help reduce or even reverse changes linked This review aims explore rela-tionship AD, with focus on IR. It explores molecular mechanisms by which IR lead assesses current treatments target Understanding IR's connection AD offers new possibilities highlights importance continued this interdisciplinary field.

Язык: Английский

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Mechanism and Therapeutic Prospect of miRNAs in Neurodegenerative Diseases

Behavioural Neurology, Год журнала: 2023, Номер 2023, С. 1 - 24

Опубликована: Ноя. 23, 2023

MicroRNAs (miRNAs) are the smallest class of noncoding RNAs, which widely exist in animals and plants. They can inhibit translation or overexpression by combining with mRNA participate posttranscriptional regulation genes, resulting reduced expression target proteins, affecting development, growth, aging, metabolism, other physiological pathological processes It is a powerful negative regulator gene expression. mediates information exchange between different cellular pathways homeostasis stress response regulates differentiation, plasticity, neurotransmission neurons. In neurodegenerative diseases, addition to complex interactions genetic susceptibility environmental factors, miRNAs serve as promising diagnostic tool for diseases. also increase reduce neuronal damage regulating body's signaling pathways, immune system, stem cells, gut microbiota, etc. not only affect occurrence diseases exacerbate disease progression but promote repair apoptosis, prevent slow down development This article reviews research progress on mechanism treatment nervous system. trial registered NCT01819545, NCT02129452, NCT04120493, NCT04840823, NCT02253732, NCT02045056, NCT03388242, NCT01992029, NCT04961450, NCT03088839, NCT04137926, NCT02283073, NCT04509271, NCT02859428, NCT05243017.

Язык: Английский

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Exploring the interplay of glucose metabolism, insulin resistance, and neurodegenerative pathologies: insights from streptozotocin and hypoglycaemic in vitro models

Journal of Neural Transmission, Год журнала: 2025, Номер unknown

Опубликована: Фев. 11, 2025

Язык: Английский

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Type 3 diabetes and metabolic reprogramming of brain neurons: causes and therapeutic strategies

Molecular Medicine, Год журнала: 2025, Номер 31(1)

Опубликована: Фев. 18, 2025

Abstract Abnormal glucose metabolism inevitably disrupts normal neuronal function, a phenomenon widely observed in Alzheimer’s disease (AD). Investigating the mechanisms of metabolic adaptation during progression has become central focus research. Considering that impaired is closely related to decreased insulin signaling and resistance, new concept "type 3 diabetes mellitus (T3DM)" been coined. T3DM specifically refers brain’s neurons becoming unresponsive insulin, underscoring strong link between AD. Recent studies reveal brain exhibit mitochondrial dysfunction, reduced metabolism, elevated lactate levels. These findings suggest caused by may lead compensatory shift toward glycolysis. Consequently, this review aims explore underlying causes elucidate how resistance drives reprogramming AD progression. Additionally, it highlights therapeutic strategies targeting sensitivity function as promising avenues for successful development treatments.

Язык: Английский

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Inducing elevated glucose levels in vitro: A model to simulate prediabetes (preDBT) states in primary cultures

Brain Behavior and Immunity, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

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Conquering Insulin Network Dysfunctions in Alzheimer’s Disease: Where Are We Today?

Journal of Alzheimer s Disease, Год журнала: 2024, Номер 101(s1), С. S317 - S343

Опубликована: Окт. 18, 2024

Functional impairments in the brain's insulin and insulin-like growth factor (IGF) signal transduction networks are recognized mediators of dysregulated energy metabolism, a major driver Alzheimer's disease (AD) neurodegeneration cascade. AD-associated insulin-deficient insulin-resistant states mimic those diabetes mellitus affect all cell types brain. Besides accounting for abundant amyloid-β hyperphosphorylated tau lesions AD, insulin/IGF pathway dysfunctions cause cortical atrophy, loss synaptic plasticity, white matter myelin/oligodendrocyte degeneration, astrocyte microglial neuroinflammation oxidative stress, deficits mitochondrial dysfunction, microvascular disease. These same neuropathological processes have been linked to cognitive impairment type 2 mellitus, Parkinson's disease, vascular dementia. Strategies address metabolic borrowed from other diseases leveraged on preclinical AD model data. The repurposing drugs led clinical trials with intranasal insulin, followed by sensitizers including metformin peroxisome-proliferator-activated receptor agonists, then incretin mimetics primarily targeting GLP-1 receptors. In addition, glucose-lowering agents tested their efficacy preventing declines. strengths limitations these approaches discussed. main conclusion this review is that we now arrived at stage which it time long-term trophic availability responsiveness, signaling abnormalities extend beyond include IGFs interconnected pathways, need multi-pronged rather than single-pronged therapeutic remediate forms neurodegeneration.

Язык: Английский

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Association between dietary soy prevention of fetal alcohol spectrum disorder and normalization of placental insulin and insulin-like growth factor signaling networks and downstream effector molecule expression

Gene & Protein in Disease, Год журнала: 2024, Номер 3(2), С. 3113 - 3113

Опубликована: Июнь 13, 2024

Chronic prenatal alcohol exposure causes fetal spectrum disorder (FASD), often associated with impaired placentation and intrauterine growth restriction. Ethanol’s inhibition of insulin insulin-like factor Type 1 (IGF-1) signaling compromises trophoblastic cell motility maternal vascular transformation at the implantation site. Previous studies have demonstrated that dietary soy effectively normalizes in an experimental model FASD. The were extended to better understand mechanisms underlying soy’s beneficial effects. Pregnant Long Evans rats pair-fed isocaloric liquid diets containing either 0% or 36% caloric ethanol from gestation day (GD) 6. protein source consisted casein (standard control) isolate. On GD19, placentas harvested measure mRNA levels corresponding major components insulin/IGF-1 pathway, as well aspartyl-asparaginyl-β-hydroxylase (ASPH), Notch, HES, which play critical roles placentation. gestational fed significantly reduced expression insulin, receptor, Igf1, IGF-1 receptor (Igf1r), substrate (Irs1), Irs2, Asph, Hes1. In addition, decreased ASPH expression. Dietary mitigated most these effects further enhanced by upregulating Igf2, Igf2r, Irs1, Irs4, Hes1 chronically exposed relative control samples. protective FASD act level positively impact pathways imperative for normal development. Gestational may provide effective means preventing vulnerable populations.

Язык: Английский

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Brain and Serum Membrane Vesicle (Exosome) Profiles in Experimental Alcohol-Related Brain Degeneration: Forging the Path to Non-Invasive Liquid Biopsy Diagnostics

Journal of Molecular Pathology, Год журнала: 2024, Номер 5(3), С. 360 - 384

Опубликована: Сен. 10, 2024

Background: Alcohol-related brain degeneration (ARBD) is associated with cognitive–motor impairments that can progress to disability and dementia. White matter (WM) prominently targeted in ARBD due chronic neurotoxic degenerative effects on oligodendrocytes myelin. Early detection monitoring of WM pathology could lead therapeutic interventions. Objective: This study examines the potential utility a non-invasive strategy for detecting using exosomes isolated from serum. Comparative analyses were made paired tissue (Tx) membrane vesicles (MVs) temporal lobe (TL). Methods: Long Evans rats fed 8 weeks isocaloric liquid diets containing 37% or 0% caloric ethanol (n = 8/group). TL-Tx, TL-MVs, serum (S-EVs) used examine ethanol’s oligodendrocyte glycoprotein, astrocyte, oxidative stress markers. Results: Ethanol significantly decreased TL-Tx expression platelet-derived growth factor receptor alpha (PDGFRA), 2′,3′-cyclic nucleotide 3′ phosphodiesterase (CNPase), proteolipid protein (PLP), myelin glycoprotein (MOG), glial fibrillary acidic (GFAP), 8-OHdG, whereas increased CNPase, PDGFRA, but MOG GFAP concordantly TL-Tx. modulated S-EV by reducing PLP, nestin, GFAP, 4-hydroxynonenal (HNE). Conclusion: Chronic exposures differentially alter oligodendrocyte/myelin, markers brain, MVs, S-EVs. However, directionally concordant across all three compartments limited. Future studies should advance these efforts characterizing relationship between ABRD molecular pathological changes WM-specific

Язык: Английский

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Dysregulated mTOR networks in experimental sporadic Alzheimer’s disease

Frontiers in Cellular Neuroscience, Год журнала: 2024, Номер 18

Опубликована: Сен. 25, 2024

Beyond the signature amyloid-beta plaques and neurofibrillary tangles, Alzheimer's disease (AD) has been shown to exhibit dysregulated metabolic signaling through insulin insulin-like growth factor (IGF) networks that crosstalk with mechanistic target of rapamycin (mTOR). Its broad impact on brain structure function suggests mTOR is likely an important therapeutic for AD. This study characterizes temporal lobe (TL) abnormalities in a rat model sporadic AD neurodegeneration. Long Evans rats were given intracerebroventricular injections streptozotocin (ic-STZ) or saline (control), 4 weeks later, they administered neurobehavioral tests followed by terminal harvesting TLs histopathological measurement biomarkers, neuroinflammatory/oxidative stress markers, total phosphorylated insulin/IGF-1-Akt-mTOR pathway molecules. Rats treated ic-STZ exhibited significantly impaired performance Rotarod (RR) Morris Water Maze (MWM) tests, atrophy, TL hippocampal neuronal white matter degeneration, elevated pTau, AβPP, Aβ, AChE, 4-HNE, GAPDH reduced ubiquitin, IL-2, IL-6, IFN-γ immunoreactivities. In addition, pY1135/1136-IGF-1R, Akt, PTEN, pS380-PTEN, pS2448-mTOR, p70S6K, pT412-p70S6K, p/T-pT412-p70S6K, p/T-Rictor, p/T-Raptor. Experimental ic-STZ-induced AD-type neurodegeneration dysfunctions associated inhibition linked energy metabolism, plasticity, integrity.

Язык: Английский

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