Neural Regeneration Research, Год журнала: 2023, Номер 19(5), С. 961 - 962
Опубликована: Авг. 14, 2023
Synaptic dysfunction: Alzheimer's disease (AD) is a prevalent form of dementia, affecting over 35 million people worldwide (Tzioras et al., 2023). A synapse serves as the connection point between neurons, facilitating transmission information from one neuron to another. Dynamic alterations in synapses, known synaptic plasticity, play pivotal role cognitive processes such learning and memory. loss has been identified key contributor decline AD patients. Studies have shown that soluble forms amyloid-beta (Aβ) tau proteins are toxic leading impairment animal models (Spires-Jones Hyman, 2014). Additionally, formation oligomers Aβ can spread pathology through connections brain, emphasizing vital synapses progression. Despite significance AD, effective treatments prevent or slow currently lacking. deeper understanding pathological changes could provide crucial biomarkers for early diagnosis treatment. Down syndrome (DS), trisomy 21, genetic disorder results an extra copy chromosome 21 part it. It most common cause intellectual developmental disabilities linked early-onset AD. Individuals with DS typically exhibit AD-like brain (DS-AD) by age 40, including amyloid plaques neurofibrillary tangles, which progress dementia 60 (Chen 2021). However, there limited research on DS-AD. Given similarities DS-AD pathology, it reasonable speculate individuals may also experience similar observed Amyloid precursor protein (APP) dose-dependent reduction DS: Neurotransmitter-containing vesicles release their contents into cleft, initiating neurons. Specific receptors postsynaptic then bind these neurotransmitters. The fusion plasma membrane requires N-ethylmaleimide-sensitive factor attachment receptor (SNARE) complex, composed vesicular SNARE synaptobrevin target syntaxin-1 synaptosomal-associated protein-25 (SNAP-25) (Sudhof, 2012). Changes core involved vesicle lead neurological dysfunction. Limited knowledge exists regarding levels distinctions While numerous reports investigated mild impairment, they uncovered inconsistent reductions various located both pre- post-synaptically. comparable underlying pathologies DS-AD, would be expected demonstrate alterations. Our revealed decreased several frontal cortex syntaxin 1A SNAP25, synaptophysin synapsin 1, well density PSD95. Notably, complex were correlated other 2023a), indicating essential necessary neurotransmitter signify dysfunction this set brains subjects consistent sporadic cases. no complexes patients without suggesting molecular cellular events defects jointly contribute potential pathogenesis comorbidities. Consistently, we notable age-dependent SNAP25 Dp16 mouse model. findings rare case partial (PT-DS) (Doran 2017) mice App gene normalization (Dp16: App++−) indicate increased dosage APP (Figure 1).Figure 1: Increased dose induces retromer subunits DS.Increased elevated its processing products, species. In but not diagnosis, dependent occurs, along complex. shows presynaptic compartments, DS, APP-dependent subunits. Aβ42 Aβ40 arising decrease subunit function, turn production. Thus, dosage-induced synergize affected pathways drive at different stages DS. Created BioRender.com. AD: disease; APP: protein; Aβ: amyloid-beta; syndrome; SNARE: receptor.Synaptic terminal contains only vesicles, variety components exocytosis endocytosis processes. One critical component responsible endosomal sorting. This recognizes specific transmembrane facilitates transport trans-Golgi network recycling back membrane. highlighted involvement neurodegenerative diseases, VPS26 VPS35 reduced. Dysfunction production Genetic studies retromer-associated SNX1, SNX3, Rab7a, SORL1/SORLA (Brodin Shupliakov, 2018). pathogenic mechanisms due expression upregulation microRNA miR-155 encoded found SNX27, resulting (Wang 2013). Moreover, hippocampal SNX27 improve deficits. Therefore, basis new strategies addressing loss. We significant VPS26A, VPS26B, VPS29 PT-DS 2023b). downregulation was 16-month-old dosage. GluA1 displayed same subunits, reflecting functions 1). To identify location isolated synaptosomes 20-month-old male 2N mice. enrichment each synaptosomes. throughout homogenate rather than cytoplasmic fraction. These suggest primary activity. Importantly, administration novel gamma-secretase modulator, designed specifically γ-site cleavages γ-secretase resulted levels, increase nontoxic Aβ38 Aβ37. treatment successfully restored VPS29, GluA1, diminished Limitations perspective: follow hierarchical pattern, function childhood young adulthood, followed AD-related neuronal later stages. latter characterized markers. worth highlighting particularly children adults, general abilities, attributed occurring brain. encompass deficits neurogenesis, maturation, synaptogenesis. strongly correlation modifications onset associated noteworthy comparatively less experiences comparison regions like entorhinal cortex. evaluate within vulnerable regions. Nevertheless, further investigations imperative ascertain whether present adults if so, elucidate changes. Furthermore, reported functional imbalance excitation inhibition, morphological enlargement spines, precise links electrophysiological features even behavioral outcomes need defined, although roles individual yet fully elucidated. Biomarkers utilized define status valuable investigate reflected corresponding body fluids. Further needed efficacy utilizing proteins, thereby enhancing our diagnostic tools. Contrarily, finding stands contrast obtained above, exhibited reduced DS-AS PT-DS. difference suggests while clinical differed. Rab5 activity characteristic feature demonstrated accelerate internalization endolysosomal system where C-terminal fragments species, (Grbovic 2003). retrieving endosomes membrane, process. accumulation detrimental effects stability consequently line this, impairs trafficking promotes cleavage β-secretase, Aβ, Aβ40. species creating positive feedback loop patterns start very stages, occur predominantly preclinical models, modulators extensively tested ability reduce making them promising therapeutic approach Gamma-secretase modulator study determine reverse proteins. Both transmission, evidenced models. still completely clear, how downstream synergistically microstructural changes, deficits, subsequent across Nonetheless, reinforce disrupting aligns requirement development C-Editors: Zhao M, Liu WJ, Qiu Y; T-Editor: Jia Y
Язык: Английский