Network Analysis of a Membrane-Enriched Brain Proteome across Stages of Alzheimer’s Disease

Previous systems-based proteomic approaches have characterized alterations in protein co-expression networks of unfractionated asymptomatic (AsymAD) and symptomatic Alzheimer’s disease (AD) brains. However, it remains unclear how sample fractionation and sub-proteomic analysis influences the organization of these protein networks and their relationship to clinicopathological traits of disease. In this proof-of-concept study, we performed a systems-based sub-proteomic analysis of membrane-enriched post-mortem brain samples from pathology-free control, AsymAD, and AD brains (n = 6 per group). Label-free mass spectrometry based on peptide ion intensity was used to quantify the 18 membrane-enriched fractions. Differential expression and weighted protein co-expression network analysis (WPCNA) were then used to identify and characterize modules of co-expressed proteins most significantly altered between the groups. We identified a total of 27 modules of co-expressed membrane-associated proteins. In contrast to the unfractionated proteome, these networks did not map strongly to cell-type specific markers. Instead, these modules were principally organized by their associations with a wide variety of membrane-bound compartments and organelles. Of these, the mitochondrion was associated with the greatest number of modules, followed by modules linked to the cell surface compartment. In addition, we resolved networks with strong associations to the endoplasmic reticulum, Golgi apparatus, and other membrane-bound organelles. A total of 14 of the 27 modules demonstrated significant correlations with clinical and pathological AD phenotypes. These results revealed that the proteins within individual compartments feature a heterogeneous array of AD-associated expression patterns, particularly during the preclinical stages of disease. In conclusion, this systems-based analysis of the membrane-associated AsymAD brain proteome yielded a unique network organization highly linked to cellular compartmentalization. Further study of this membrane-associated proteome may reveal novel insight into the complex pathways governing the earliest stages of disease.

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Label-free high-resolution proteomic analysis of cerebrospinal fluid in Alzheimer's disease

IBRO Reports ◽

10.1016/j.ibror.2019.07.697 ◽

2019 ◽

Vol 6 ◽

pp. S223-S224

Author(s):

Sun Ah Park ◽

Jin Myung Jung ◽

Jun Sung Park ◽

Jeong Ho Lee ◽

Bumhee Park ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

High Resolution ◽

Proteomic Analysis ◽

Label Free

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Selective Secretase Targeting for Alzheimer’s Disease Therapy

Journal of Alzheimer s Disease ◽

10.3233/jad-201027 ◽

2021 ◽

pp. 1-17

Author(s):

Alvaro Miranda ◽

Enrique Montiel ◽

Henning Ulrich ◽

Cristian Paz

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Amyloid Plaques ◽

Neuroprotective Activity ◽

Amyloid Β Protein ◽

Secretase Activity ◽

Membrane Bound ◽

Aβ Production ◽

Bace 1

Alzheimer’s disease (AD) is associated with marked atrophy of the cerebral cortex and accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are formed by oligomers of amyloid-β (Aβ) in the brain, with a length of 42 and 40 amino acids. α-secretase cleaves amyloid-β protein precursor (AβPP) producing the membrane-bound fragment CTFα and the soluble fragment sAβPPα with neuroprotective activity; β-secretase produces membrane-bound fragment CTFβ and a soluble fragment sAβPPβ. After α-secretase cleavage of AβPP, γ-secretase cleaves CTFα to produce the cytoplasmic fragment AICD and P3 in the non-amyloidogenic pathway. CTFβ is cleaved by γ-secretase producing AICD as well as Aβ in amyloidogenic pathways. In the last years, the study of natural products and synthetic compounds, such as α-secretase activity enhancers, β-secretase inhibitors (BACE-1), and γ-secretase activity modulators, have been the focus of pharmaceuticals and researchers. Drugs were improved regarding solubility, blood-brain barrier penetration, selectivity, and potency decreasing Aβ42. In this regard, BACE-1 inhibitors, such as Atabecestat, NB-360, Umibecestat, PF-06751979, Verubecestat, LY2886721, Lanabecestat, LY2811376, and Elenbecestat, were submitted to phase I-III clinical trials. However, inhibition of Aβ production did not recover cognitive functions or reverse the disease. Novel strategies are being developed, aiming at a partial reduction of Aβ production, such as the development of γ-secretase modulators or α-secretase enhancers. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and the activities of the latest compounds designed for AD treatment, with remarkable in vitro, in vivo, and clinical phase activities.

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Shared Blood Transcriptomic Signatures between Alzheimer’s Disease and Diabetes Mellitus

Biomedicines ◽

10.3390/biomedicines9010034 ◽

2021 ◽

Vol 9 (1) ◽

pp. 34

Author(s):

Taesic Lee ◽

Hyunju Lee

Keyword(s):

Diabetes Mellitus ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protein Interactions ◽

Expression Patterns ◽

Protein Protein Interactions ◽

Hub Genes ◽

Gene Modules ◽

Gene Regulatory ◽

The Brain

Alzheimer’s disease (AD) and diabetes mellitus (DM) are known to have a shared molecular mechanism. We aimed to identify shared blood transcriptomic signatures between AD and DM. Blood expression datasets for each disease were combined and a co-expression network was used to construct modules consisting of genes with similar expression patterns. For each module, a gene regulatory network based on gene expression and protein-protein interactions was established to identify hub genes. We selected one module, where COPS4, PSMA6, GTF2B, GTF2F2, and SSB were identified as dysregulated transcription factors that were common between AD and DM. These five genes were also differentially co-expressed in disease-related tissues, such as the brain in AD and the pancreas in DM. Our study identified gene modules that were dysregulated in both AD and DM blood samples, which may contribute to reveal common pathophysiology between two diseases.

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Microglial Function and Regulation during Development, Homeostasis and Alzheimer’s Disease

Cells ◽

10.3390/cells10040957 ◽

2021 ◽

Vol 10 (4) ◽

pp. 957

Author(s):

Brad T. Casali ◽

Erin G. Reed-Geaghan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Immune Cells ◽

Expression Patterns ◽

Brain Parenchyma ◽

Primary Role ◽

And Function ◽

Inflammatory Milieu ◽

The Brain ◽

Homeostatic State

Microglia are the resident immune cells of the brain, deriving from yolk sac progenitors that populate the brain parenchyma during development. During development and homeostasis, microglia play critical roles in synaptogenesis and synaptic plasticity, in addition to their primary role as immune sentinels. In aging and neurodegenerative diseases generally, and Alzheimer’s disease (AD) specifically, microglial function is altered in ways that significantly diverge from their homeostatic state, inducing a more detrimental inflammatory environment. In this review, we discuss the receptors, signaling, regulation and gene expression patterns of microglia that mediate their phenotype and function contributing to the inflammatory milieu of the AD brain, as well as strategies that target microglia to ameliorate the onset, progression and symptoms of AD.

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