Molecular and Cellular Mechanisms of Synaptopathies: Emerging Synaptic aging-related molecular pathways in Neurological Disorders

H.R QUINTÁ; LAURA IBANEZ; CRUCHAGA, C.; DARIO MASCHI

Frontiers in Aging Neuroscience

Frontiers Media SA.

Lugar: Lauzana; Año: 2023

Despite the enormous advances made in our understanding of neurological disorders, aknowledge gap still exists that prevents the scientific community from linking clinicalmanifestations with actual cellular neuropathological changes. This connection is especiallycrucial for pathologies like Alzheimer´s disease (AD), which has a 10–20 year preclinical periodoffering an extended window for potential interventions (McKhann et al. 1984; Sperling et al.2011). However, the preclinical period has been challenging to explore due to the lack of specificprognostic and predictive biomarkers.To identify disease progression biomarkers, we must diligently explore and identify newcausal genes and pathways associated with the disease. Furthermore, by understanding thesepathologies´ mechanistic, we will speed up the development of new disease-modifyingtherapies. Future advances in this endeavor will necessitate the collaborative efforts ofresearchers from diverse backgrounds. This diversity is reflected in our editorial panel andamong the contributors to this topic. Our Frontiers Research Topic, entitled ´Molecular andCellular Mechanisms of Synaptopathies: Emerging Synaptic Aging-Related Molecular Pathwaysin Neurological Disorders,´ comprises original research articles from experts in the neurosciencefield. These experts explore novel brain disease-related pathways that could serve as potentialtherapeutic targets. The number and originality of these contributions highlight the interest andongoing activity in this area of investigation.Among the promising new pharmacological discoveries, Bellanti et al. highlights thetherapeutic potential of ultramicronized palmitoylethanolamide (um-PEA) in AD. Chronicum-PEA treatment improved mitochondrial function and restored energy metabolism in thefrontal cortex of mice, suggesting um-PEA treatment as a potential novel strategy for futureclinical treatment of AD due to its bioenergetic effects.Nan et al. offer valuable insights regarding the intersection of metabolic disorders andneurodegenerative diseases. Increasing evidence points towards a potential connectionbetween diabetes and AD. Diabetes can lead to cognitive impairment and brain changes suchas altered synaptic plasticity, aggregated amyloid-beta (Aβ) plaques, and neurofibrillary tanglescomposed of hyperphosphorylated tau protein. Given the demographic trend toward globalaging and that the incidence of diabetes has been steadily rising, the significance of theirresearch is clear. They examine the pathogenesis of post-menopausal diabetic encephalopathyand propose Forsythoside⋅B as an effective a therapeutic agent.Expanding our understanding of the role of age in cognitive health, Li et al. present a novel research perspective on the impact of young plasma on anesthesia and surgery-induced cognitive impairment in aged rats. Their study reveals a compelling connection between youngplasma preinfusion and a reduction in such cognitive impairments. Thus, young plasmaemerges as a potential therapeutic strategy to mitigate cognitive dysfunction linked to surgeryand anesthesia in the aged population.A remarkable example of a promising study that uncovers new treatment possibilities forneurodegenerative pathologies is the work of León et al. They explore the potential of c-Abltyrosine kinase as a therapeutic target in AD pathogenesis. In previous work, Dr. Alvarez, thelead author, had collaborated with Dr. Marugan from the National Center for AdvancingTranslational Sciences (NCATS) to develop neurotinib, a novel c-Abl inhibitor capable ofcrossing the blood-brain barrier. Here, they demonstrate that down-regulating c-Abl leads toimproved cognitive performance and reduced neuropathological symptoms in AD mousemodels, marking neurotinib as a promising candidate for AD therapy.Delving into the intricate mechanisms behind protein misfolding, Cazzaro et al. contributesignificantly to our understanding of the disease propagation in AD. They study the mechanismsthat govern the secretion of small extracellular vesicles containing misfolded proteins. Theirfindings reveal that Slingshot Homolog-1 augments this secretion, suggesting a promisingapproach to promoting the degradation of misfolded proteins and curbing the spread ofintercellular pathology.In an effort to understand how AD pathology affects neuronal activity, Martinsson et al. haveshown that elevated levels of Aβ and its precursor protein, the amyloid precursor protein (APP),induce increased neuronal activity in AD. Specifically, they found impaired adaptation of calciumtransients to global activity changes and observed that neurons failed to adjust the length oftheir axon initial segments, which typically affects excitability. They hypothesize that the closelocalization of APP and Aβ near synapses may play a vital role in the altered synapticresponses. These insights point to potential treatment strategies focusing on earlyAβ/APP-induced hyperexcitability and synapse dysfunction.Underscoring the importance of synaptic health in neurodegenerative disease, Olajide et al.show that amyloid beta peptide 1–42 causes significant mitochondrial dysfunction atglutamatergic synapses, leading to rapid synapse alterations, reduced energy productionefficiency, and a significant reduction in key mitochondrial and synaptic protein expression.Notably, they show that lowering reactive oxygen species prevents synaptic impairments. Thisimplies that therapies targeting reactive oxygen species might help curb the advancement ofneurodegeneration in chronic models of AD.Zhang et al. shift our attention to the protective potential of naturally occurring compounds inneurodegenerative diseases. They show that polyphenols in oolong tea have neuroprotectiveIn reviewand anti-aging activities, nominating them as potential therapeutic agents for age-relatedneurodegenerative diseases.Pursuing further insights into the role of protein aggregates, Ferrari et al. shed light on theimpact of soluble α-synuclein oligomers in Parkinson´s disease, finding that these oligomers playa central role in the early events leading to synaptic loss. This discovery could offer newavenues for early detection and potential therapeutic interventions, underscoring the importanceof comprehending the role of these oligomers in the onset of Parkinson´s Disease and relateddisorders.As we conclude this brief overview of the featured articles in our Research Topics, we want todraw attention to the work by Carbonell et al. They used quantitative mass spectrometry tocompare hippocampal synaptic proteomes across different Autism Spectrum Disorder (ASD)mouse models, identifying shared alterations in cellular and molecular pathways at the synapse.These results suggest that diverse ASD-related genes may converge on shared synapticsignaling pathways, paving the way for a better understanding of the pathogenesis of not justASD but also other neuropathologies.Addressing neurodegenerative diseases remains a critical challenge of our era, furtherintensified by an aging population, increasing disease prevalence, and lack ofdisease-modifying therapies and good biomarkers. Vital to mitigating these conditions isstrategically targeting the early stages of disease progression to prevent irreversible neuronalloss and increase therapeutic effectiveness. However, this is often hindered by the fact that theirsymptoms frequently remain undetected until the later stages, and our knowledge of themolecular events that initiate these diseases is still limited. Despite these difficulties, theinnovative approaches and unwavering commitment demonstrated by the researcherscontributing to this topic reflect the ongoing strides made to unravel these diseases´complexities and propose out-of-the-box therapeutic targets advancing the field towardpersonalized medicine. As we continue to gain novel insights and explore new pathways, we are confident in our collective ability to advance our understanding and ultimately turn the tide against neurodegenerative diseases.