Alzheimer's disease (AD) is a debilitating neurodegenerative disease characterized by the accumulation of extracellular amyloid-β peptides (Aβ) within the cerebral parenchyma and vasculature, which ...is known as cerebral amyloid angiopathy (CAA). This study utilized confocal imaging to investigate heparan sulfate (HS) expression within the cerebrovasculature and its associations with Aβ, gender, and ApoE4 genotype in AD. Our investigation revealed elevated levels of HS in the cerebrovasculature of AD patients with severe CAA. Additionally, these patients exhibited higher HS colocalization with Aβ in the cerebrovasculature, including both endothelial and vascular smooth muscle cell compartments. Intriguingly, a reversal in the polarized expression of HS within the cerebrovasculature was detected in AD patients with severe CAA. Furthermore, male patients exhibited lower levels of both parenchymal and cerebrovascular HS. Additionally, ApoE4 carriers displayed heightened cerebrovascular Aβ expression and a tendency of elevated cerebrovascular HS levels in AD patients with severe CAA. Overall, these findings reveal potential intricate interplay between HS, Aβ, ApoE, and vascular pathology in AD, thereby underscoring the potential roles of cerebrovascular HS in CAA development and AD pathology. Further study of the underlying mechanisms may present novel therapeutic avenues for AD treatment.
The cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a common histopathological hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia disease ...spectrum (ALS/FTD). However, the composition of aggregates and their contribution to the disease process remain unknown. Here we used proximity-dependent biotin identification (BioID) to interrogate the interactome of detergent-insoluble TDP-43 aggregates and found them enriched for components of the nuclear pore complex and nucleocytoplasmic transport machinery. Aggregated and disease-linked mutant TDP-43 triggered the sequestration and/or mislocalization of nucleoporins and transport factors, and interfered with nuclear protein import and RNA export in mouse primary cortical neurons, human fibroblasts and induced pluripotent stem cell-derived neurons. Nuclear pore pathology is present in brain tissue in cases of sporadic ALS and those involving genetic mutations in TARDBP and C9orf72. Our data strongly implicate TDP-43-mediated nucleocytoplasmic transport defects as a common disease mechanism in ALS/FTD.
Electrodes that provide brain to machine or computer interfacing must survive the lifetime of the person to be considered an acceptable prosthetic. The electrodes may be external such as with ...electroencephalographic (EEG), internal extracortical such as electrocorticographic (ECoG) or intracortical.
Most intracortical electrodes are placed close to the neuropil being recorded and do not survive years of recording. However, the Neurotrophic Electrode is placed within the cortex and the neuropil grows inside and through the hollow tip of the electrode and is thus trapped inside. Highly flexible coiled lead wires minimize the strain on the electrode tip. Histological analysis includes immunohistochemical detection of neurofilaments and the absence of gliosis.
This configuration led to a decade long recording in this locked-in person. At year nine, the neural activity underwent conditioning experiments indicating that the neural activity was functional and not noise. This paper presents data on the histological analysis of the tissue inside the electrode tip after 13 years of implantation.
This paper is a singular example of histological analysis after a decade of recording. The histological analysis laid out herein is strong evidence that the brain can grow neurites into the electrode tip and record for a decade. This is profoundly important in the field of brain to machine or computer interfacing by implying that long term electrodes should incorporate some means of growing the neuropil into the electrode rather than placing the electrode into the neuropil.
Objective
Neuroimaging and other biomarker assays suggest that the pathological processes of Alzheimer's disease (AD) begin years prior to clinical dementia onset. However, some 30 to 50% of older ...individuals who harbor AD pathology do not become symptomatic in their lifetime. It is hypothesized that such individuals exhibit cognitive resilience that protects against AD dementia. We hypothesized that in cases with AD pathology, structural changes in dendritic spines would distinguish individuals who had or did not have clinical dementia.
Methods
We compared dendritic spines within layer II and III pyramidal neuron dendrites in Brodmann area 46 dorsolateral prefrontal cortex using the Golgi–Cox technique in 12 age‐matched pathology‐free controls, 8 controls with AD pathology (CAD), and 21 AD cases. We used highly optimized methods to trace impregnated dendrites from bright‐field microscopy images that enabled accurate 3‐dimensional digital reconstruction of dendritic structure for morphologic analyses.
Results
Spine density was similar among control and CAD cases but was reduced significantly in AD. Thin and mushroom spines were reduced significantly in AD compared to CAD brains, whereas stubby spine density was decreased significantly in CAD and AD compared to controls. Increased spine extent distinguished CAD cases from controls and AD. Linear regression analysis of all cases indicated that spine density was not associated with neuritic plaque score but did display negative correlation with Braak staging.
Interpretation
These observations provide cellular evidence to support the hypothesis that dendritic spine plasticity is a mechanism of cognitive resilience that protects older individuals with AD pathology from developing dementia. Ann Neurol 2017;82:602–614
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share phenotypic and pathologic overlap. Recently, an expansion of GGGGCC repeats in the first intron of C9orf72 was found to be ...a common cause of both illnesses; however, the molecular pathogenesis of this expanded repeat is unknown. Here we developed both Drosophila and mammalian models of this expanded hexanucleotide repeat and showed that expression of the expanded GGGGCC repeat RNA (rGGGGCC) is sufficient to cause neurodegeneration. We further identified Pur α as the RNA-binding protein of rGGGGCC repeats and discovered that Pur α and rGGGGCC repeats interact in vitro and in vivo in a sequence-specific fashion that is conserved between mammals and Drosophila . Furthermore, overexpression of Pur α in mouse neuronal cells and Drosophila mitigates rGGGGCC repeat-mediated neurodegeneration, and Pur α forms inclusions in the fly eye expressing expanded rGGGGCC repeats, as well as in cerebellum of human carriers of expanded GGGGCC repeats. These data suggest that expanded rGGGGCC repeats could sequester specific RNA-binding protein from their normal functions, ultimately leading to cell death. Taken together, these findings suggest that the expanded rGGGGCC repeats could cause neurodegeneration, and that Pur α may play a role in the pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia.
Chaperone-mediated autophagy controls the degradation of selective cytosolic proteins and may protect neurons against degeneration. In a neuronal cell line, we found that chaperone-mediated autophagy ...regulated the activity of myocyte enhancer factor 2D (MEF2D), a transcription factor required for neuronal survival. MEF2D was observed to continuously shuttle to the cytoplasm, interact with the chaperone Hsc70, and undergo degradation. Inhibition of chaperone-mediated autophagy caused accumulation of inactive MEF2D in the cytoplasm. MEF2D levels were increased in the brains of α-synuclein transgenic mice and patients with Parkinson's disease. Wild-type α-synuclein and a Parkinson's disease-associated mutant disrupted the MEF2D-Hsc70 binding and led to neuronal death. Thus, chaperone-mediated autophagy modulates the neuronal survival machinery, and dysregulation of this pathway is associated with Parkinson's disease.
Although the genetic causes for several rare, familial forms of Alzheimer's disease (AD) have been identified, the etiology of the sporadic form of AD remains unclear. Here, we report a systems-level ...study of disease-associated proteome changes in human frontal cortex of sporadic AD patients using an integrated approach that combines mass spectrometry-based quantitative proteomics, differential expression analysis, and co-expression network analysis. Our analyses of 16 human brain tissues from AD patients and age-matched controls showed organization of the cortical proteome into a network of 24 biologically meaningful modules of co-expressed proteins. Of these, 5 modules are positively correlated to AD phenotypes with hub proteins that are up-regulated in AD, and 6 modules are negatively correlated to AD phenotypes with hub proteins that are down-regulated in AD. Our study generated a molecular blueprint of altered protein networks in AD brain and uncovered the dysregulation of multiple pathways and processes in AD brain, including altered proteostasis, RNA homeostasis, immune response, neuroinflammation, synaptic transmission, vesicular transport, cell signaling, cellular metabolism, lipid homeostasis, mitochondrial dynamics and function, cytoskeleton organization, and myelin-axon interactions. Our findings provide new insights into AD pathogenesis and suggest novel candidates for future diagnostic and therapeutic development.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlap in clinical presentation, neuropathology, and genetic underpinnings. The molecular ...basis for the overlap of these disorders is not well established. We performed a comparative unbiased mass spectrometry‐based proteomic analysis of frontal cortical tissues from postmortem cases clinically defined as ALS, FTD, ALS and FTD (ALS/FTD), and controls. We also included a subset of patients with the C9orf72 expansion mutation, the most common genetic cause of both ALS and FTD. Our systems‐level analysis of the brain proteome integrated both differential expression and co‐expression approaches to assess the relationship of these differences to clinical and pathological phenotypes. Weighted co‐expression network analysis revealed 15 modules of co‐expressed proteins, eight of which were significantly different across the ALS‐FTD disease spectrum. These included modules associated with RNA binding proteins, synaptic transmission, and inflammation with cell‐type specificity that showed correlation with TDP‐43 pathology and cognitive dysfunction. Modules were also examined for their overlap with TDP‐43 protein–protein interactions, revealing one module enriched with RNA‐binding proteins and other causal ALS genes that increased in FTD/ALS and FTD cases. A module enriched with astrocyte and microglia proteins was significantly increased in ALS cases carrying the C9orf72 mutation compared to sporadic ALS cases, suggesting that the genetic expansion is associated with inflammation in the brain even without clinical evidence of dementia. Together, these findings highlight the utility of integrative systems‐level proteomic approaches to resolve clinical phenotypes and genetic mechanisms underlying the ALS‐FTD disease spectrum in human brain.
Synopsis
A systems‐level quantitative analysis of the brain proteome reveals pathways and cell types underlying clinicopathological phenotypes across the amyotrophic lateral sclerosis and frontotemporal dementia (ALS‐FTD) disease spectrum, further linking the C9orf72 mutation to neuroinflammation.
Human brain protein expression has a molecular signature distinguishing clinical phenotype along the ALS‐FTD disease spectrum.
Co‐expression revealed modules associated with RNA binding proteins, synaptic transmission, and inflammation with strong correlation to TDP‐43 pathology and cognitive dysfunction.
A module enriched with microglial markers, TDP‐43 protein–protein interactions, and causal ALS gene products implicates novel drivers of disease.
An astrocyte and microglia module differentiates ALS cases with the C9orf72 mutation from sporadic ALS cases, linking the genetic expansion with neuroinflammation.
A systems‐level quantitative analysis of the brain proteome reveals pathways and cell types underlying clinicopathological phenotypes across the amyotrophic lateral sclerosis and frontotemporal dementia (ALS‐FTD) disease spectrum, further linking the C9orf72 mutation to neuroinflammation.
Patients with Alzheimer's disease (AD) and Parkinson's disease (PD) often have overlap in clinical presentation and brain neuropathology suggesting that these two diseases share common underlying ...mechanisms. Currently, the molecular pathways linking AD and PD are incompletely understood. Utilizing Tandem Mass Tag (TMT) isobaric labeling and synchronous precursor selection-based MS3 (SPS-MS3) mass spectrometry, we performed an unbiased quantitative proteomic analysis of post-mortem human brain tissues (n=80) from four different groups defined as controls, AD, PD, and co-morbid AD/PD cases across two brain regions (frontal cortex and anterior cingulate gyrus). In total, we identified 11 840 protein groups representing 10 230 gene symbols, which map to ~65% of the protein coding genes in brain. The utility of including two reference standards in each TMT 10-plex assay to assess intra- and inter-batch variance is also described. Ultimately, this comprehensive human brain proteomic dataset serves as a valuable resource for various research endeavors including, but not limited to, the identification of disease-specific protein signatures and molecular pathways that are common in AD and PD.
Here, we report proteomic analyses of 129 human cortical tissues to define changes associated with the asymptomatic and symptomatic stages of Alzheimer’s disease (AD). Network analysis revealed 16 ...modules of co-expressed proteins, 10 of which correlated with AD phenotypes. A subset of modules overlapped with RNA co-expression networks, including those associated with neurons and astroglial cell types, showing altered expression in AD, even in the asymptomatic stages. Overlap of RNA and protein networks was otherwise modest, with many modules specific to the proteome, including those linked to microtubule function and inflammation. Proteomic modules were validated in an independent cohort, demonstrating some module expression changes unique to AD and several observed in other neurodegenerative diseases. AD genetic risk loci were concentrated in glial-related modules in the proteome and transcriptome, consistent with their causal role in AD. This multi-network analysis reveals protein- and disease-specific pathways involved in the etiology, initiation, and progression of AD.
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•Protein modules correlated with cognition and Alzheimer’s disease (AD) pathology•Modules associated with brain cell types overlapped in protein and RNA networks•Many protein-based modules were distinct from those in RNA-directed networks•AD risk loci converged in glial-related modules in the proteome and transcriptome
Using label-free “single shot” proteomics, we define changes in the proteome of human brain linked to preclinical and clinical stages of Alzheimer’s disease (AD). These data reveal modules of co-expressed proteins that correlate with AD phenotypes, are distinct from modules identified from gene co-expression data, and highlight non-neuronal drivers of disease.
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