Nature Reviews Bioengineering, Год журнала: 2024, Номер 2(8), С. 691 - 709
Опубликована: Июнь 5, 2024
Язык: Английский
Advanced Science, Год журнала: 2024, Номер 11(12)
Опубликована: Янв. 18, 2024
Abstract In Alzheimer's disease (AD), dysfunctional mitochondrial metabolism is associated with synaptic loss, the major pathological correlate of cognitive decline. Mechanistic insight for this relationship, however, still lacking. Here, comparing isogenic wild‐type and AD mutant human induced pluripotent stem cell (hiPSC)‐derived cerebrocortical neurons (hiN), evidence found compromised energy in using Seahorse platform to analyze glycolysis oxidative phosphorylation (OXPHOS). Isotope‐labeled metabolic flux experiments revealed a block activity tricarboxylic acid (TCA) cycle at α‐ketoglutarate dehydrogenase (αKGDH)/succinyl coenzyme‐A synthetase step, metabolizing succinate. Associated block, aberrant protein S‐nitrosylation αKGDH subunits inhibited their enzyme function. This documented not only AD‐hiN but also postmortem brains versus controls, as assessed by two separate unbiased mass spectrometry platforms both SNOTRAP identification S‐nitrosothiols chemoselective‐enrichment S‐nitrosoproteins. Treatment dimethyl succinate, cell‐permeable derivative TCA substrate downstream resulted partial rescue bioenergetic function well reversal synapse loss AD‐hiN. These findings have therapeutic implications that can ameliorate hiPSC‐based models AD.
Язык: Английский
Процитировано
11
Journal of Clinical Medicine, Год журнала: 2024, Номер 13(2), С. 536 - 536
Опубликована: Янв. 17, 2024
Background: The concept of Alzheimer disease (AD)—since its histological discovery by to the present day—has undergone substantial modifications. Methods: We conducted a classical narrative review this field with bibliography selection (giving preference Medline best match). Results: following subjects are reviewed and discussed: Alzheimer’s discovery, Kraepelin’s creation new that was rare condition until 1970′s, growing interest investment in AD as major killer society large elderly population second half 20th century, consolidation clinicopathological model, modern nosology based on dominant amyloid hypothesis among many others. In 21st development biomarkers has supported novel biological definition AD, although proposed therapies have failed cure disease. incidence dementia/AD shown decrease affluent countries (possibly due control risk factors), mixed dementia been established most frequent etiology oldest old. Conclusions: current lacks unanimity. Many hypotheses attempt explain complex physiopathology entwined aging, cascade yielded poor therapeutic results. reduction appears promising but it should be confirmed future. A reevaluation is also necessary.
Язык: Английский
Процитировано
10
BMC Medicine, Год журнала: 2024, Номер 22(1)
Опубликована: Март 25, 2024
Abstract Background Synaptic dysfunction with reduced synaptic protein levels is a core feature of Alzheimer’s disease (AD). proteins play central role in memory processing, learning, and AD pathogenesis. Evidence suggests that plasma neuronal-derived extracellular vesicles (EVs) are patients AD. However, it remains unclear whether EVs associated hippocampal atrophy upregulating the expression these has beneficial effect on Methods In this study, we included 57 56 healthy controls. We evaluated their brain through magnetic resonance imaging using medial temporal lobe score. measured four proteins, including synaptosome-associated 25 (SNAP25), growth-associated 43 (GAP43), neurogranin, synaptotagmin 1 both cerebrospinal fluid (CSF). further examined association atrophy. also brains 5×FAD mice. Then, loaded rabies virus glycoprotein-engineered messenger RNAs (mRNAs) encoding GAP43 SNAP25 administered to After treatment, dendritic density, cognitive function were evaluated. Results The results showed GAP43, SNAP25, decreased but increased CSF AD, changes corresponded severity engineered efficiently stably delivered brain, where markedly upregulated. Upregulation could ameliorate impairment by promoting density. This marks first successful delivery mRNAs via mice, yielding remarkable therapeutic effects. Conclusions closely related processes. Delivery stands as promising effective precision treatment strategy for which significantly advances current understanding approaches disease.
Язык: Английский
Процитировано
8
Journal of Alzheimer s Disease, Год журнала: 2024, Номер 98(4), С. 1169 - 1179
Опубликована: Апрель 9, 2024
Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of neurofibrillary tangles and amyloid-β plaques. Recent research has unveiled pivotal role insulin signaling dysfunction in pathogenesis AD. Insulin, once thought to be unrelated brain function, emerged as crucial factor neuronal survival, synaptic plasticity, cognitive processes. Insulin downstream molecules are found mainly hippocampus cortex. Some responsible for GSK-3β, Akt, PI3K, IRS. Irregularities or resistance may arise from changes phosphorylation levels key molecules, which can influenced both stimulation inactivity. This, turn, believed contributing development AD, oxidative stress, neuroinflammation, other pathological hallmarks. Furthermore, this route known indirectly Nrf2, NF-κB, caspases. This mini-review delves into intricate relationship between exploring how disruptions pathway contribute progression. Moreover, we examine recent advances drug delivery systems designed target AD treatment. From oral innovative nanoparticle approaches intranasal administration, these strategies hold promise mitigating impact on review consolidates current knowledge shed light potential interventions targeted therapeutic options
Язык: Английский
Процитировано
8
Nature Reviews Bioengineering, Год журнала: 2024, Номер 2(8), С. 691 - 709
Опубликована: Июнь 5, 2024
Язык: Английский
Процитировано
8