Dendritic Spine and Synaptic Plasticity in Alzheimer's Disease: A Focus on MicroRNA.

Dendrites and dendritic spines are dynamic structures with pivotal roles in brain connectivity and have been recognized as the locus of long-term synaptic plasticity related to cognitive processes such as learning and memory. In neurodegenerative diseases, the spine dynamic morphology alteration, such as shape and spine density, affects functional characteristics leading to synaptic dysfunction and cognitive impairment. Recent evidence implicates dendritic spine dysfunction as a critical feature in the pathogenesis of dementia, particularly Alzheimer's disease. The alteration of spine morphology and their loss is correlated with the cognitive decline in Alzheimer's disease patients even in the absence of neuronal loss, however, the underlying mechanisms are poorly understood. Currently, the microRNAs have emerged as essential regulators of synaptic plasticity. The changes in neuronal microRNA expression that contribute to the modification of synaptic function through the modulation of dendritic spine morphology or by regulating the local protein translation to synaptic transmission are determinant for synapse formation and synaptic plasticity. Focusing on microRNA and its targets may provide insight into new therapeutic opportunities. In this review we summarize the experimental evidence of the role that the microRNA plays in dendritic spine remodeling and synaptic plasticity and its potential therapeutic approach in Alzheimer's disease. Targeting synaptic deficits through the structural alteration of dendritic spines could form part of therapeutic strategies to improve synaptic plasticity and to ameliorate cognitive impairments in Alzheimer's disease and other neurological diseases.

Infection Mechanism of SARS-COV-2 and Its Implication on the Nervous System.

In late December 2019, multiple atypical pneumonia cases resulted in severe acute respiratory syndrome caused by a pathogen identified as a novel coronavirus SARS-CoV-2. The most common coronavirus disease 2019 (COVID-19) symptoms are pneumonia, fever, dry cough, and fatigue. However, some neurological complications following SARS-CoV-2 infection include confusion, cerebrovascular diseases, ataxia, hypogeusia, hyposmia, neuralgia, and seizures. Indeed, a growing literature demonstrates that neurotropism is a common feature of coronaviruses; therefore, the infection mechanisms already described in other coronaviruses may also be applicable for SARS-CoV-2. Understanding the underlying pathogenetic mechanisms in the nervous system infection and the neurological involvement is essential to assess possible long-term neurological alteration of COVID-19. Here, we provide an overview of associated literature regarding possible routes of COVID-19 neuroinvasion, such as the trans-synapse-connected route in the olfactory pathway and peripheral nerve terminals and its neurological implications in the central nervous system.

Potential Effects of MSC-Derived Exosomes in Neuroplasticity in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common type of dementia affecting regions of the central nervous system that exhibit synaptic plasticity and are involved in higher brain functions such as learning and memory. AD is characterized by progressive cognitive dysfunction, memory loss and behavioral disturbances of synaptic plasticity and energy metabolism. Cell therapy has emerged as an alternative treatment of AD. The use of adult stem cells, such as neural stem cells and Mesenchymal Stem Cells (MSCs) from bone marrow and adipose tissue, have the potential to decrease cognitive deficits, possibly by reducing neuronal loss through blocking apoptosis, increasing neurogenesis, synaptogenesis and angiogenesis. These processes are mediated primarily by the secretion of many growth factors, anti-inflammatory proteins, membrane receptors, microRNAs (miRNA) and exosomes. Exosomes encapsulate and transfer several functional molecules like proteins, lipids and regulatory RNA which can modify cell metabolism. In the proteomic characterization of the content of MSC-derived exosomes, more than 730 proteins have been identified, some of which are specific cell type markers and others are involved in the regulation of binding and fusion of exosomes with adjacent cells. Furthermore, some factors were found that promote the recruitment, proliferation and differentiation of other cells like neural stem cells. Moreover, within exosomal cargo, a wide range of miRNAs were found, which can control functions related to neural remodeling as well as angiogenic and neurogenic processes. Taking this into consideration, the use of exosomes could be part of a strategy to promote neuroplasticity, improve cognitive impairment and neural replacement in AD. In this review, we describe how exosomes are involved in AD pathology and discuss the therapeutic potential of MSC-derived exosomes mediated by miRNA and protein cargo.

Data set of interactomes and metabolic pathways of proteins differentially expressed in brains with Alzheimer׳s disease.

Alzheimer׳s disease is one of the main causes of dementia in the elderly and its frequency is on the rise worldwide. It is considered the result of complex interactions between genetic and environmental factors, being many of them unknown. Therefore, there is a dire necessity for the identification of novel molecular players for the understanding of this disease. In this data article we determined the protein expression profiles of whole protein extracts from cortex regions of brains from patients with Alzheimer׳s disease in comparison to a normal brain. We identified 721 iTRAQ-labeled polypeptides with more than 95% in confidence. We analyzed all proteins that changed in their expression level and located them in the KEGG metabolic pathways, as well as in the mitochondrial complexes of the electron transport chain and ATP synthase. In addition, we analyzed the over- and sub-expressed polypeptides through IPA software, specifically Core I and Biomarkers I modules. Data in this article is related to the research article "Identification of proteins that are differentially expressed in brains with Alzheimer's disease using iTRAQ labeling and tandem mass spectrometry" (Minjarez et al., 2016) [1].

Identification of proteins that are differentially expressed in brains with Alzheimer's disease using iTRAQ labeling and tandem mass spectrometry.

Alzheimer's disease is one of the leading causes of dementia in the elderly. It is considered the result of complex events involving both genetic and environmental factors. To gain further insights into this complexity, we quantitatively analyzed the proteome of cortex region of brains from patients diagnosed with Alzheimer's disease, using a bottom-up proteomics approach. We identified 721 isobaric-tagged polypeptides. From this universe, 61 were found overexpressed and 69 subexpressed in three brains with Alzheimer's disease in comparison to a normal brain. We determined that the most affected processes involving the overexpressed polypeptides corresponded to ROS and stress responses. For the subexpressed polypeptides, the main processes affected were oxidative phosphorylation, organellar acidification and cytoskeleton. We used Drosophila to validate some of the hits, particularly those non-previously described as connected with the disease, such as Sideroflexin and Phosphoglucomutase-1. We manipulated their homolog genes in Drosophila models of Aß- and Tau-induced pathology. We found proteins that can either modify Aß toxicity, Tau toxicity or both, suggesting specific interactions with different pathways. This approach illustrates the potential of Drosophila to validate hits after MS studies and suggest that model organisms should be included in the pipeline to identify relevant targets for Alzheimer's disease. BIOLOGICAL SIGNIFICANCE: We report a set of differentially expressed proteins in three Alzheimer's disease brains in comparison to a normal brain. Our analyses allowed us to identify that the main affected pathways were ROS and stress responses, oxidative phosphorylation, organellar acidification and cytoskeleton. We validated some identified proteins using genetic models of Amyloid-ß and Tau-induced pathology in Drosophila melanogaster. With this approach, Sideroflexin and Phosphoglucomutase-1 were identified as novel proteins connected with Alzheimer's disease.

Identification of polypeptides in neurofibrillary tangles and total homogenates of brains with Alzheimer's disease by tandem mass spectrometry.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. AD brains are characterized by the presence of neurofibrillary tangles (NFTs) and neuritic plaques. NFTs are constituted of paired helical filaments, which are structurally composed by assembled hyperphosphorylated and truncated tau polypeptides. To date, the integral constituents of NFTs remain unknown mainly due to the high insolubility of NFTs. The aim of this study was to identify by tandem mass spectrometry, the polypeptides contained in both isolated NFTs by laser capture microdissection and total homogenates, using tissue sections from paraformaldehyde-fixed AD brains. In the first case, we isolated 2,000 NFTs from tissue samples of hippocampus from each of the three Mexican AD brains used in our study. These were previously stained with anti-hyperphosphorylated tau AT-100 antibodies. After the removal of paraformaldehyde and delipidation with organic solvents, we tested three solubilization methods. We identified 102 polypeptides from total homogenates and 41 from isolated NFTs. We selected UCH-L1, transferrin, and GAPDH polypeptides to be studied by immunofluorescence and confocal microscopy. Only UCH-L1 and GAPDH colocalized with hyperphosphorylated tau in NFTs.