Single‐Cell Patch‐Clamp/Proteomics of Human Alzheimer's Disease iPSC‐Derived Excitatory Neurons Versus Isogenic Wild‐Type Controls Suggests Novel Causation and Therapeutic Targets

Advanced Science, Journal Year: 2024, Volume and Issue: 11(29)

Published: May 21, 2024

Abstract Standard single‐cell (sc) proteomics of disease states inferred from multicellular organs or organoids cannot currently be related to physiology. Here, a scPatch‐Clamp/Proteomics platform is developed on single neurons generated hiPSCs bearing an Alzheimer's (AD) genetic mutation and compares them isogenic wild‐type controls. This approach provides both current voltage electrophysiological data plus detailed information single‐cells. With this new method, the authors are able observe hyperelectrical activity in AD hiPSC‐neurons, similar that observed human brain, correlate it ≈1400 proteins detected at neuron level. Using linear regression mediation analyses explore relationship between abundance individual neuron's mutational status, yields therapeutic targets excitatory not attainable by traditional methods. combined patch‐proteomics technique creates proteogenetic‐therapeutic strategy genotypic alterations physiology with protein expression

Language: Английский

---

Redox imbalance and metabolic defects in the context of Alzheimer disease

FEBS Letters, Journal Year: 2024, Volume and Issue: unknown

Published: March 12, 2024

Redox reactions play a critical role for intracellular processes, including pathways involved in metabolism and signaling. Reactive oxygen species (ROS) act either as second messengers or generators of protein modifications, fundamental mechanisms signal transduction. Disturbance redox homeostasis is associated with many disorders. Among these, Alzheimer's disease neurodegenerative pathology that presents hallmarks oxidative damage such increased ROS production, decreased activity antioxidant enzymes, modifications macromolecules, changes mitochondrial homeostasis. Interestingly, alteration closely defects energy metabolism, involving both carbohydrates lipids, the major fuels cell. As brain relies exclusively on glucose utilization represent harmful event brain. During aging, progressive perturbation occurs resulting hypometabolism. This condition contributes to increase neuronal cell vulnerability ultimately cognitive impairment. The current review discusses crosstalk between seems concert promoting neurodegeneration.

Language: Английский

---

Coenzyme Q10 alleviates AlCl3 and D-galactose induced Alzheimer via modulating oxidative burden and TLR-4/MAPK pathways and regulation microRNA in rat brain

Toxicology Research, Journal Year: 2025, Volume and Issue: 14(2)

Published: March 1, 2025

Alzheimer's disease (ad) is the most progressive form of neurodegenerative resulting in cognitive and non-cognitive deficits. Coenzyme Q10 (CoQ10) an anti-inflammatory anti-oxidative stress supplement that can improve inflammation oxidative associated with ad. This study aimed to explore protective potential coenzyme (CoQ10). It also sought uncover any synergistic effects when combined donepezil, acetylcholinesterase inhibitor, treating rats, focusing on modulation TLR-4/MAPK pathway regulation microRNA. The experiment involved seventy rats categorized into different groups: control, Reference group (donepezil 10 mg/kg/P.O.), CoQ10 alone (1,200 ad-model (D-galactose (120 mg/kg/i.p) + Alcl3 (50 mg/kg/P.O.)), donepezil co-treatment, co-treatment. Behavioral parameter was defined using Morris-Maze test (MMT) various assessments, such as GABA, stress, Aβ1-42, ion homeostasis, toll-like receptor-4 (TLR-4), mitogen-activated protein kinase-1 (MAPK-1), micro-RNA (mir-106b, mir-107, mir-9) were measured. Immunohistological staining used assess structural abnormalities hippocampus. treatment demonstrated memory improvement, enhanced locomotion, increased neuronal differentiation, mainly through activation mir-106b, mir-9. improved rats' passive avoidance impairment caused by D-gal AlCl3. ad led alteration pathways.CoQ10 a agent, diminishes burden, homeostasis.CoQ10 counteracts enhancing neurotransmitter regulating MicroRNA.CoQ10 lowered accumulation Aβ plaque hippocampal neurons D-Gal AlCl3-treated rats.One promising therapeutic method combination therapy.

Language: Английский

---

Oligomer sensitive in-situ detection and characterization of gold colloid aggregate formations observed within the hippocampus of the Alzheimer’s disease rat

Neuroscience Letters, Journal Year: 2025, Volume and Issue: unknown, P. 138218 - 138218

Published: March 1, 2025

Language: Английский

---

Redox chemical delivery system: an innovative strategy for the treatment of neurodegenerative diseases

Expert Opinion on Drug Delivery, Journal Year: 2025, Volume and Issue: unknown

Published: April 5, 2025

It is anticipated that the prevalence of illnesses affecting central nervous system (CNS) will rise significantly due to longer lifespans and changing demography. Age-related decline in brain function neuronal death are features neurodegenerative disorders, such as Parkinson's disease, Alzheimer's Huntington's amyotrophic lateral sclerosis, which provide formidable treatment challenges. Because most therapeutic drugs cannot pass across blood-brain barrier (BBB) reach brain, there still few alternatives available despite a great deal research. This study explores role redox chemical delivery systems CNS drug addresses challenges associated with disease (ND). Redox Chemical Delivery System offers promising approach enhancing leveraging reactions facilitate transport agents BBB. Through optimization medication pathways this technology has potential greatly improve ND. As our understanding biological underpinnings ND deepens, for effective interventions increases. Refining strategies, RCDS, essential advancing therapies from research clinical practice. These advancements could transform management ND, improving both efficacy patient outcomes.

Language: Английский

---

COVID-19 and Alzheimer’s Disease Share Common Neurological and Ophthalmological Manifestations: A Bidirectional Risk in the Post-Pandemic Future

Cells, Journal Year: 2023, Volume and Issue: 12(22), P. 2601 - 2601

Published: Nov. 10, 2023

A growing body of evidence indicates that a neuropathological cross-talk takes place between the coronavirus disease 2019 (COVID-19) -the pandemic severe pneumonia has had tremendous impact on global economy and health since three years after its outbreak in December 2019- Alzheimer’s Disease (AD), leading cause dementia among human beings, reaching 139 million by year 2050. Even though COVID-19 is primary respiratory disease, causative agent, so-called Severe Acute Respiratory Syndrome 2 (SARS-CoV-2), also endowed with high neuro-invasive potential (Neurocovid). The neurological complications COVID-19, resulting from direct viral entry into Central Nervous System (CNS) and/or indirect systemic inflammation dysregulated activation immune response, encompass memory decline anosmia which are typically associated AD symptomatology. In addition, patients diagnosed more vulnerable to SARS-CoV-2 infection inclined clinical outcomes. present review, we better elucidate intimate connection summarizing involved risk factors/targets underlying biological mechanisms shared these two disorders particular focus Angiotensin-Converting Enzyme (ACE2) receptor, APOlipoprotein E (APOE), aging, neuroinflammation cellular pathways Amyloid Precursor Protein (APP)/Amyloid beta (Aβ) tau neuropathologies. Finally, involvement ophthalmological manifestations, including vitreo-retinal abnormalities visual deficits, both discussed. Understanding common physiopathological aspects linking will pave way novel management diagnostic/therapeutic approaches cope them post-pandemic future.

Language: Английский

---

Sex- and region-specific cortical and hippocampal whole genome transcriptome profiles from control and APP/PS1 Alzheimer’s disease mice

PLoS ONE, Journal Year: 2024, Volume and Issue: 19(2), P. e0296959 - e0296959

Published: Feb. 7, 2024

A variety of Alzheimer’s disease (AD) mouse models has been established and characterized within the last decades. To get an integrative view sophisticated etiopathogenesis AD, whole genome transcriptome studies turned out to be indispensable. Here we carried microarray data collection based on RNA extracted from retrosplenial cortex hippocampus age-matched, eight months old male female APP/PS1 AD mice control animals perform sex- brain region specific analysis profiles. The results our reveal novel, detailed insight into differentially expressed signature genes related fold changes in individual subgroups. Gene ontology Venn unmasked that intersectional, upregulated were predominantly involved in, e.g., activation microglial, astrocytic neutrophilic cells, innate immune response/immune effector response, neuroinflammation, phagosome/proteasome activation, synaptic transmission. number (intersectional) downregulated was substantially less different subgroups GO categories included, vesicle docking/fusion machinery, transmission, rRNA processing, ubiquitination, proteasome degradation, histone modification cellular senescence. Importantly, this is first study systematically unravel region-specific fingerprints/signature mice. latter will central relevance future preclinical clinical studies, biomarker characterization personalized medicinal approaches.

Language: Английский

---

Mitochondrial Complex I and β-Amyloid Peptide Interplay in Alzheimer’s Disease: A Critical Review of New and Old Little Regarded Findings

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(21), P. 15951 - 15951

Published: Nov. 3, 2023

Alzheimer's disease (AD) is the most common neurodegenerative disorder and main cause of dementia which characterized by a progressive cognitive decline that severely interferes with daily activities personal life. At pathological level, it accumulation abnormal protein structures in brain-β-amyloid (Aβ) plaques Tau tangles-which interfere communication between neurons lead to their dysfunction death. In recent years, research on AD has highlighted critical involvement mitochondria-the primary energy suppliers for our cells-in onset progression disease, since mitochondrial bioenergetic deficits precede beginning mitochondria are very sensitive Aβ toxicity. On other hand, if true leads malfunctions, otherwise proven dysfunction, through generation reactive oxygen species, causes an increase production, initiating vicious cycle: there therefore bidirectional relationship aggregation dysfunction. Here, we focus latest news-but also neglected evidence from past-concerning interplay dysfunctional complex I, oxidative stress, Aβ, order understand how implicated pathogenesis disease.

Language: Английский

---

Mitochondrial vulnerability to oxidation in human brain organoids modelling Alzheimer's disease

Free Radical Biology and Medicine, Journal Year: 2023, Volume and Issue: 208, P. 394 - 401

Published: Aug. 30, 2023

Language: Английский

---

Neuronal glutathione depletion elevates the Aβ42/Aβ40 ratio and tau aggregation in Alzheimer's disease mice

FEBS Letters, Journal Year: 2024, Volume and Issue: 598(13), P. 1576 - 1590

Published: May 24, 2024

Alzheimer's disease (AD) involves reduced glutathione levels, causing oxidative stress and contributing to neuronal cell death. Our prior research identified diminished glutamate‐cysteine ligase catalytic subunit (GCLC) as linked However, the effect of GCLC on AD features such amyloid tau pathology remained unclear. To address this, we investigated in mice by combining neuron‐specific conditional knockout with precursor protein ( App ) knockin (KI) or microtubule‐associated MAPT KI mice. Intriguingly, resulted an increased Aβ42/40 ratio. Additionally, deficiency accelerated oligomerization through intermolecular disulfide bonds. These findings suggest that decline due aging pathology, may contribute progression AD.

Language: Английский

---