Profiling the human hippocampal proteome at all pathologic stages of Alzheimer's disease

Hondius, David; Nierop, Pim van; Li, Ka Wan; Hoozemans, Jeroen J. M.; Schors, Roel C. van der; Haastert, Elise S. van; Vies, Saskia M. van der; Rozemüller, Annemieke; Smit, August B.

doi:10.1016/j.jalz.2015.11.002

Cited by 139 publications

(153 citation statements)

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“…Notably, Aß affects synapse loss in AD hippocampus by disruption of Ncam2 [22] and overexpression of wild-type PS1 or PS1 with a familial AD mutation (M146L) leads to decreased sialylation of Ncam in the neuroblastoma cell line SH-SY5Y [23]. Recently, Hondius et al demonstrated that the human post-mortem AD hippocampus has an altered expression of a number of proteins associated with extracellular matrix components and calcium-dependent signalling proteins that are linked to early changes in cytoskeletal dynamics and synaptic plasticity over the different Braak stages compared to matched controls [24]. …”

Section: Discussionmentioning

confidence: 99%

An integrated proteomics approach shows synaptic plasticity changes in an APP/PS1 Alzheimer's mouse model

et al. 2016

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The aim of this study was to elucidate the molecular signature of Alzheimer's disease-associated amyloid pathology.We used the double APPswe/PS1ΔE9 mouse, a widely used model of cerebral amyloidosis, to compare changes in proteome, including global phosphorylation and sialylated N-linked glycosylation patterns, pathway-focused transcriptome and neurological disease-associated miRNAome with age-matched controls in neocortex, hippocampus, olfactory bulb and brainstem. We report that signalling pathways related to synaptic functions associated with dendritic spine morphology, neurite outgrowth, long-term potentiation, CREB signalling and cytoskeletal dynamics were altered in 12 month old APPswe/PS1ΔE9 mice, particularly in the neocortex and olfactory bulb. This was associated with cerebral amyloidosis as well as formation of argyrophilic tangle-like structures and microglial clustering in all brain regions, except for brainstem. These responses may be epigenetically modulated by the interaction with a number of miRNAs regulating spine restructuring, Aβ expression and neuroinflammation.We suggest that these changes could be associated with development of cognitive dysfunction in early disease states in patients with Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

An integrated proteomics approach shows synaptic plasticity changes in an APP/PS1 Alzheimer's mouse model

et al. 2016

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“…Among 372 altered proteins, several ECM components were increased in AD, including tenascin, versican, laminin subunit beta-2, and galectin-1. In addition, increases in adhesion molecules that interact with ECM, including CD44, integrin β1, and integrin αV were observed in AD [134]. In contrast, versican and tenascin-R were significantly decreased in frontal cortex AD brain tissue [135].…”

Section: Changes In Brain Ecm In Neurodegenerative Conditionsmentioning

confidence: 99%

“…Intriguingly, versican, one of the hyalectans, was differentially expressed in three out of six studies [78, 134, 135], reporting differential expression of ECM proteins. Notably, all three studies were performed as shotgun proteomics experiments, with label-free LC-MS/MS analysis, using an LTQ-Orbitrap instrument.…”

Section: Current State Of Proteomics In Studies Of Neurodegenerative mentioning

confidence: 99%

“…2. A study [135] identified 8% sequence coverage (yellow), while another study [134], identified 17% sequence coverage (red). Major domains covered by these studies were Ig-like V-type (21-146), link 1(150-245), link 2 (251-347), EGF-like 2, calcium binding (3176-3290) and c-type lectin (3294-3354) domains.…”

Section: Current State Of Proteomics In Studies Of Neurodegenerative mentioning

confidence: 99%

“…Peptide sequence coverage for Versican protein, identified by previous studies [135] ( yellow) and [134] (red). Domain (blue numbers), Ig-like V-type; 21-146; link 1; 150-245, link 2; 251-347, EGF-like 1; 3089-3125, EGF-like 2, calcium binding; 3127-3163, c-type lectin; 3176-3290, Sushi; 3294-3354.…”

Section: Figmentioning

confidence: 99%

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Extracellular matrix proteomics in schizophrenia and Alzheimer’s disease

Sethi

Zaia

2016

Anal Bioanal Chem

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Brain extracellular matrix (ECM) is a highly organized system that consists of collagens, non-collagenous proteins, glycoproteins, hyaluronan and proteoglycans (PGs). Recognized physiological roles of ECM include developmental regulation, tissue homeostasis, cell migration, proliferation, differentiation, neuronal plasticity, and neurite outgrowth. Aberrant ECM structure is associated with brain neurodegenerative conditions. This review focuses on two neurodegenerative conditions, schizophrenia (Sz) and Alzheimer's disease (AD), and summarizes recent findings of altered ECM components, including PGs, glycosaminoglycans (GAGs), proteins and glycoproteins, and proteins and genes related to other brain components. The scope includes immunohistochemical, genomics, transcriptomics, proteomics and glycomics studies, and a critical assessment of current state of proteomics studies for neurodegenerative disorders. The intent is to summarize the ECM molecular alterations associated with neurodegenerative pathophysiology.

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Pathophysiological subtypes of Alzheimer’s disease based on cerebrospinal fluid proteomics

Tijms

Visser

2020

Alzheimer's & Dementia

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Background Alzheimer’s disease (AD) is a biologically heterogeneous disorder. Cerebrospinal fluid (CSF) contains thousands of proteins, with concentrations reflecting ongoing (patho)physiological processes. This provides the opportunity to study many biological processes at the same time in patients. Using a dual clustering technique, non‐negative matrix factorization, we studied whether biological subtypes of AD can be detected in CSF proteomics in two independent cohorts, and we will provide an overview how subtypes differed on biological clinical characteristics. Method We selected individuals with AD (defined as abnormal ab42 in CSF) and controls (normal cognition and normal AD biomarkers) from ADNI and the EMIF‐AD biomarker multimodality biomarker discovery study (ADNI: 32 preclinical AD, 103 prodromal AD, 62 AD‐dementia, 45 controls; EMIF‐AD: 56 preclinical AD, 90 prodromal AD, 77 AD‐dementia, and 82 controls). In ADNI we studied 149 proteins measured with mass reaction monitoring spectrometry and a multiplex rules based medicine assay, and in EMIF‐AD 556 proteins measured with tandem‐mass tag spectrometry. Proteins were selected when concentrations differed between AD and controls, scaled to include only positive values and then clustered with non‐negative matrix factorisation. Subtypes were compared on demographical, clinical and protein CSF markers not used for clustering. Result Both cohorts showed three protein profiles, based on which we allocated individuals to three subtypes: In EMIF‐AD, subtype 1 included 80 individuals (36%), subtype 2 included 71 individuals (32%) and subtype 3included 72 individuals (32%). In ADNI, subtype 1 included 97 individuals (45%), subtype 2 included 69 individuals (35%) and subtype 3 included 39 individuals (20%). Gene Ontology (GO) pathway analysis showed that proteins specifically increased in subtype 1 were enriched for synapse functioning, in subtype 2 for innate immune system activation and in subtype 3 for blood‐brain barrier dysfunction (all pFDR <0.05). Compared to controls, subtypes showed overlapping and distinct regional atrophy patterns: subtype 1 atrophy showed most pronounced atrophy in temporal areas; subtype 2 showed more involvement of parietal areas, and subtype 3 of frontal areas. Conclusion Biological heterogeneity amongst individuals with AD can be robustly detected with CSF proteomics, and this provides new opportunities for development of patient tailored treatment approaches.

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Profiling the human hippocampal proteome at all pathologic stages of Alzheimer's disease

Abstract: This study provides new insight into AD-dependent changes in protein levels in the hippocampus during AD pathology, identifying potential novel therapeutic targets and biomarkers.

Cited by 139 publications

References 54 publications

An integrated proteomics approach shows synaptic plasticity changes in an APP/PS1 Alzheimer's mouse model

An integrated proteomics approach shows synaptic plasticity changes in an APP/PS1 Alzheimer's mouse model

Extracellular matrix proteomics in schizophrenia and Alzheimer’s disease

Pathophysiological subtypes of Alzheimer’s disease based on cerebrospinal fluid proteomics

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