Proteomic signatures of brain regions affected by tau pathology in early and late stages of Alzheimer's disease

Mendonça, Clarissa Ferolla; Kuras, Magdalena; Nogueira, Fábio César Sousa; Plá, Indira; Hortobágyi, Tibor; Csiba, László; Palkóvits, M.; Renner, Éva; Döme, Péter; Markó-Varga, György; Domont, Gilberto B.; Rezeli, Melinda

doi:10.1016/j.nbd.2019.104509

Cited by 54 publications

(67 citation statements)

References 65 publications

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“…A recent proteomic analysis of human brain specimens was performed to better understand the vulnerability of specific brain regions to AD. The medial temporal lobe, which includes the hippocampus, was shown to have prominent oxidative phosphorylation impairment compared to the neocortex [60]. The differential effect of the compound in the hippocampus and forebrain of htau mice may partially reflect some of the proteomic differences observed in these published studies.…”

Section: Discussionmentioning

confidence: 89%

In Vivo Validation of a Small Molecule Inhibitor of Tau Self-Association in htau Mice

Davidowitz

Krishnamurthy

Lopez

et al. 2020

JAD

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Tau oligomers have been shown to transmit tau pathology from diseased neurons to healthy neurons through seeding, tau misfolding, and aggregation that is thought to play an influential role in the progression of Alzheimer's disease (AD) and related tauopathies. To develop a small molecule therapeutic for AD and related tauopathies, we have developed in vitro and cellular assays to select molecules inhibiting the first step in tau aggregation, the self-association of tau into oligomers. In vivo validation studies of an optimized lead compound were independently performed in the htau mouse model of tauopathy that expresses the human isoforms of tau without inherited tauopathy mutations that are irrelevant to AD. Treated mice did not show any adverse events related to the compound. The lead compound significantly reduced the level of self-associated tau and total and phosphorylated insoluble tau aggregates. The dose response was linear with respect to levels of compound in the brain. A confirmatory study was performed with male htau mice that gave consistent results. The results validated our screening approach by showing that targeting tau self-association can inhibit the entire tau aggregation pathway by using the selected and optimized lead compound whose activity translated from in vitro and cellular assays to an in vivo model of tau aggregation.

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Section: Discussionmentioning

confidence: 89%

In Vivo Validation of a Small Molecule Inhibitor of Tau Self-Association in htau Mice

Davidowitz

Krishnamurthy

Lopez

et al. 2020

JAD

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“…MTL substructures are the earliest regions affected by AD pathology, mainly amyloid deposition, and neurofibrillary tangle tau pathology. Anatomically, WM degeneration in AD follows the topographic progression of cortical AD pathology (49,50). As mentioned above, AD pathological invasion was initially localized in MTL, and then gradually spread to the temporal, parietal, and frontal lobes.…”

Section: Discussionmentioning

confidence: 91%

Long Longitudinal Tract Lesion Contributes to the Progression of Alzheimer's Disease

Luo

Qin

et al. 2020

Front. Neurol.

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Background: The degenerative pattern of white matter (WM) microstructures during Alzheimer's disease (AD) and its relationship with cognitive function have not yet been clarified. The present research aimed to explore the alterations of the WM microstructure and its impact on amnestic mild cognitive (aMCI) and AD patients. Mechanical learning methods were used to explore the validity of WM microstructure lesions on the classification in AD spectrum disease. Methods: Neuropsychological data and diffusion tensor imaging (DTI) images were collected from 28 AD subjects, 31 aMCI subjects, and 27 normal controls (NC). Tract-based spatial statistics (TBSS) were used to extract diffusion parameters in WM tracts. We performed ANOVA analysis to compare diffusion parameters and clinical features among the three groups. Partial correlation analysis was used to explore the relationship between diffusion metrics and cognitive functions controlling for age, gender, and years of education. Additionally, we performed the support vector machine (SVM) classification to determine the discriminative ability of DTI metrics in the differentiation of aMCI and AD patients from controls. Results: As compared to controls or aMCI patients, AD patients displayed widespread WM lesions, including in the inferior longitudinal fasciculus, inferior fronto-occipital fasciculi, and superior longitudinal fasciculus. Significant correlations between fractional anisotropy (FA), mean diffusivity (MD), and radial diffusion (RD) of the long longitudinal tract and memory deficits were found in aMCI and AD groups, respectively. Furthermore, through SVM classification, we found DTI indicators generated by FA and MD parameters can effectively distinguish AD patients from the control group with accuracy rates of up to 89 and 85%, respectively. Conclusion: The WM microstructure is extensively disrupted in AD patients, and the WM integrity of the long longitudinal tract is closely related to memory, which would hold Luo et al. Long Longitudinal Tract and AD potential value for monitoring the progression of AD. The method of classification based on SVM and WM damage features may be objectively helpful to the classification of AD diseases.

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“…'Protein processing in endoplasmic reticulum' was enriched in upregulated genes across all groups (App4mo, APP5mo and APP6mo). In contrast, 'oxidative phosphorylation', a process commonly considered disrupted in AD [15], was enriched in downregulated genes across all groups. Transcriptional profiling was performed just prior to or at onset of plaque onset in the B6.APP/PS1 model, which implies that modulation of metabolic processes, protein processing in the endoplasmic reticulum and oxidative phosphorylation are early events relevant to AD in this model.…”

Section: Generalized Linear Modeling Of Brain Transcriptomes From B6mentioning

confidence: 82%

Staging Alzheimer’s disease in the brain and retina of B6.APP/PS1 mice by transcriptional profiling

Chintapaludi

Uyar

Jackson

et al. 2019

Preprint

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Alzheimer's disease (AD) is a common form of dementia characterized by amyloid plaque deposition, TAU pathology, neuroinflammation and neurodegeneration. Mouse models recapitulate some key features of AD. For instance, the B6.APP/PS1 model (carrying human transgenes for mutant forms of APP and PSEN1) shows plaque deposition and associated neuroinflammatory responses involving both astrocytes and microglia beginning around 6 months of age. However, in our colony, TAU pathology, significant neurodegeneration and cognitive decline are not apparent in this model even at older ages. Therefore, this model is ideal for studying neuroinflammatory responses to amyloid deposition. Here, RNA sequencing of brain and retinal tissue, generalized linear modeling (GLM), functional annotation followed by validation by immunofluorescence (IF) was performed in B6.APP/PS1 mice to determine the earliest molecular changes prior to and around the onset of plaque deposition (2-6 months of age). Multiple pathways were shown to be activated in response to amyloid deposition including the JAK/STAT and NALFD pathways. Putative, cell-specific targets of STAT3, a central component of the JAK/STAT pathway, were identified that we propose provide more precise options for assessing the potential for targeting activation of the JAK/STAT pathway as a treatment for human AD. In the retina, GLM predicted activation of vascular-related pathways. However, many of the gene expression changes comparing B6 with B6.APP/PS1 retina samples occurred prior to plaque onset (2 months of age). This suggests retinal changes in B6.APP/PS1 mice may be an artefact of overexpression of mutant forms of APP and PSEN1 providing limited translatability to human AD. Therefore, caution should be taken when using this mouse model to assess the potential of using the eye as a window to the brain for AD. 4

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Proteomic signatures of brain regions affected by tau pathology in early and late stages of Alzheimer's disease

Cited by 54 publications

References 65 publications

In Vivo Validation of a Small Molecule Inhibitor of Tau Self-Association in htau Mice

In Vivo Validation of a Small Molecule Inhibitor of Tau Self-Association in htau Mice

Long Longitudinal Tract Lesion Contributes to the Progression of Alzheimer's Disease

Staging Alzheimer’s disease in the brain and retina of B6.APP/PS1 mice by transcriptional profiling

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