scholarly journals Integrative glycoproteomics reveals protein N-glycosylation aberrations and glycoproteomic network alterations in Alzheimer’s disease

2020 ◽  
Vol 6 (40) ◽  
pp. eabc5802
Author(s):  
Qi Zhang ◽  
Cheng Ma ◽  
Lih-Shen Chin ◽  
Lian Li
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Brain ◽  
Large Scale ◽  
Site Occupancy ◽  
Glycosylation Site ◽  
System Level ◽  
Disease Signatures ◽  
And Control

Protein N-glycosylation plays critical roles in controlling brain function, but little is known about human brain N-glycoproteome and its alterations in Alzheimer’s disease (AD). Here, we report the first, large-scale, site-specific N-glycoproteome profiling study of human AD and control brains using mass spectrometry–based quantitative N-glycoproteomics. The study provided a system-level view of human brain N-glycoproteins and in vivo N-glycosylation sites and identified disease signatures of altered N-glycopeptides, N-glycoproteins, and N-glycosylation site occupancy in AD. Glycoproteomics-driven network analysis showed 13 modules of co-regulated N-glycopeptides/glycoproteins, 6 of which are associated with AD phenotypes. Our analyses revealed multiple dysregulated N-glycosylation–affected processes and pathways in AD brain, including extracellular matrix dysfunction, neuroinflammation, synaptic dysfunction, cell adhesion alteration, lysosomal dysfunction, endocytic trafficking dysregulation, endoplasmic reticulum dysfunction, and cell signaling dysregulation. Our findings highlight the involvement of N-glycosylation aberrations in AD pathogenesis and provide new molecular and system-level insights for understanding and treating AD.

scholarly journals Neuropathological correlates and genetic architecture of microglial activation in elderly human brain

2018 ◽  
Author(s):  
Daniel Felsky ◽  
Tina Roostaei ◽  
Kwangsik Nho ◽  
Shannon L. Risacher ◽  
Elizabeth M. Bradshaw ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Brain ◽  
Cognitive Decline ◽  
Genetic Architecture ◽  
Microglial Activation ◽  
Brain Health ◽  
Positron Emission ◽  
Genome Wide

AbstractMicroglia, the resident immune cells of the brain, have important roles in brain health. However, little is known about the regulation and consequences of microglial activation in the aging human brain. We assessed the effect of microglial activation in the aging human brain by calculating the proportion of activated microglia (PAM), based on morphologically defined stages of activation in four regions sampled postmortem from up to 225 elderly individuals. We found that cortical and not subcortical PAM measures were strongly associated with β-amyloid, tau-related neuropathology, and rates of cognitive decline. Effect sizes for PAM measures are substantial, comparable to that of APOE ɛ4, the strongest genetic risk factor for Alzheimer’s disease. Mediation modeling suggests that PAM accelerates accumulation of tau pathology leading to cognitive decline, supporting an upstream role for microglial activation in Alzheimer’s disease. Genome-wide analyses identified a common variant (rs2997325) influencing cortical PAM that also affected in vivo microglial activation measured by positron emission tomography using [11C]-PBR28 in an independent cohort. Finally, we identify overlaps of PAM’s genetic architecture with those of Alzheimer’s disease, educational attainment, and several other traits.

scholarly journals In vivo human molecular neuroimaging of dopaminergic vulnerability along the Alzheimer’s disease phases

2021 ◽  
Author(s):  
Daniela Perani ◽  
Arianna Sala ◽  
Silvia Paola Caminiti ◽  
Luca Presotto ◽  
Andrea Pilotto ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Neuropsychiatric Symptoms ◽  
System Level ◽  
Binding Potential ◽  
Control Group ◽  
Molecular Connectivity ◽  
Dice Coefficient

Abstract Background Preclinical and pathology evidence suggest an involvement of brain dopamine (DA) circuitry in Alzheimer’s Disease (AD). We in vivo investigated, if, when and in which target regions, DA signaling and molecular connectivity are damaged along the AD course. Methods We retrospectively selected 16 amyloid-positive subjects with mild cognitive impairment due to AD (AD-MCI), 22 amyloid-positive patients with probable AD dementia (AD-D) and 74 healthy controls, all with available [123I]FP-CIT-SPECT imaging. We tested whether nigrostriatal vs. mesocorticolimbic dopaminergic targets present binding potential loss, via MANCOVA, and alterations in molecular connectivity, via partial-correlation analysis. Results were deemed significant at p<0.05, after Bonferroni correction for multiple comparisons. Results We found significant reductions of dopamine transporter density in both AD-MCI and AD-D compared to controls. Dopaminergic deficits were prominent in the major targets of the ventrotegmental-mesocorticolimbic pathway, namely the ventral striatum and the hippocampus, in both clinical groups, and in the cingulate gyrus, in patients with dementia only. Within the nigrostriatal projections, only the dorsal caudate nucleus showed reduced dopaminergic transporter density, in both groups. Molecular connectivity assessment revealed a widespread loss of inter-connections among subcortical and cortical targets of the mesocorticolimbic network only (poor overlap with the control group as expressed by a Dice coefficient < 0.25), and no alterations of the nigrostriatal network (high overlap with controls, Dice coefficient = 1). Conclusion Local and system-level alterations of the mesocorticolimbic dopaminergic circuitry characterize AD, already in prodromal disease phases. These results might foster new therapeutic strategies for AD. The clinical correlates of these findings deserve to be carefully considered within the emergence of both neuropsychiatric symptoms and cognitive deficits.

scholarly journals In vivo human molecular neuroimaging of dopaminergic vulnerability along the Alzheimer’s disease phases

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Arianna Sala ◽  
Silvia Paola Caminiti ◽  
Luca Presotto ◽  
Andrea Pilotto ◽  
Claudio Liguori ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Neuropsychiatric Symptoms ◽  
System Level ◽  
Binding Potential ◽  
Control Group ◽  
Molecular Connectivity ◽  
Dice Coefficient

Abstract Background Preclinical and pathology evidence suggests an involvement of brain dopamine (DA) circuitry in Alzheimer’s disease (AD). We in vivo investigated if, when, and in which target regions [123I]FP-CIT-SPECT regional binding and molecular connectivity are damaged along the AD course. Methods We retrospectively selected 16 amyloid-positive subjects with mild cognitive impairment due to AD (AD-MCI), 22 amyloid-positive patients with probable AD dementia (AD-D), and 74 healthy controls, all with available [123I]FP-CIT-SPECT imaging. We tested whether nigrostriatal vs. mesocorticolimbic dopaminergic targets present binding potential loss, via MANCOVA, and alterations in molecular connectivity, via partial correlation analysis. Results were deemed significant at p < 0.05, after Bonferroni correction for multiple comparisons. Results We found significant reductions of [123I]FP-CIT binding in both AD-MCI and AD-D compared to controls. Binding reductions were prominent in the major targets of the ventrotegmental-mesocorticolimbic pathway, namely the ventral striatum and the hippocampus, in both clinical groups, and in the cingulate gyrus, in patients with dementia only. Within the nigrostriatal projections, only the dorsal caudate nucleus showed reduced [123I]FP-CIT binding, in both groups. Molecular connectivity assessment revealed a widespread loss of inter-connections among subcortical and cortical targets of the mesocorticolimbic network only (poor overlap with the control group as expressed by a Dice coefficient ≤ 0.25) and no alterations of the nigrostriatal network (high overlap with controls, Dice coefficient = 1). Conclusion Local- and system-level alterations of the mesocorticolimbic dopaminergic circuitry characterize AD, already in prodromal disease phases. These results might foster new therapeutic strategies for AD. The clinical correlates of these findings deserve to be carefully considered within the emergence of both neuropsychiatric symptoms and cognitive deficits.

scholarly journals What Happens with the Circuit in Alzheimer's Disease in Mice and Humans?

2018 ◽  
Vol 41 (1) ◽  
pp. 277-297 ◽  
Author(s):  
Benedikt Zott ◽  
Marc Aurel Busche ◽  
Reisa A. Sperling ◽  
Arthur Konnerth
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Large Scale ◽  
Neuronal Excitability ◽  
Neuronal Damage ◽  
Strong Support ◽  
Underlying Disease ◽  
Electrophysiological Recordings

A major mystery of many types of neurological and psychiatric disorders, such as Alzheimer's disease (AD), remains the underlying, disease-specific neuronal damage. Because of the strong interconnectivity of neurons in the brain, neuronal dysfunction necessarily disrupts neuronal circuits. In this article, we review evidence for the disruption of large-scale networks from imaging studies of humans and relate it to studies of cellular dysfunction in mouse models of AD. The emerging picture is that some forms of early network dysfunctions can be explained by excessively increased levels of neuronal activity. The notion of such neuronal hyperactivity receives strong support from in vivo and in vitro cellular imaging and electrophysiological recordings in the mouse, which provide mechanistic insights underlying the change in neuronal excitability. Overall, some key aspects of AD-related neuronal dysfunctions in humans and mice are strikingly similar and support the continuation of such a translational strategy.

scholarly journals The Acetylcholine Index: An Electroencephalographic Marker of Cholinergic Activity in the Living Human Brain Applied to Alzheimer's Disease and Other Dementias

2014 ◽  
Vol 39 (3-4) ◽  
pp. 132-142 ◽  
Author(s):  
Magnus Johannsson ◽  
Jon Snaedal ◽  
Gisli Holmar Johannesson ◽  
Thorkell Eli Gudmundsson ◽  
Kristinn Johnsen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Brain ◽  
Elderly Subjects ◽  
Cholinergic Activity ◽  
Healthy Elderly ◽  
Age Related ◽  
General Decline ◽  
Using Data

Background: The cholinergic hypothesis is well established and has led to the development of pharmacological treatments for Alzheimer's disease (AD). However, there has previously been no physiological means of monitoring cholinergic activity in vivo. Methods: An electroencephalography (EEG)-based acetylcholine (Ach) index reflecting the cholinergic activity in the brain was developed using data from a scopolamine challenge study. The applicability of the Ach index was examined in an elderly population of healthy controls and patients suffering from various causes of cognitive decline. Results: The Ach index showed a strong reduction in the severe stages of AD dementia. A high correlation was demonstrated between the Ach index and cognitive function. The index was reduced in patients with mild cognitive impairment and prodromal AD, indicating a decreased cholinergic activity. When considering the distribution of the Ach index in a population of healthy elderly subjects, an age-related threshold was revealed, beyond which there is a general decline in cholinergic activity. Conclusions: The EEG-based Ach index provides, for the first time, a physiological means of monitoring the cholinergic activity in the human brain in vivo. This has great potential for aiding diagnosis and patient stratification as well as for monitoring disease progression and treatment response. © 2014 S. Karger AG, Basel

scholarly journals COMBINING MACHINE LEARNING WITH AUTOMATED NEMATODE LIFESPAN ANALYSIS TO IDENTIFY MODIFIERS OF ALZHEIMER’S DISEASE

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S96-S96
Author(s):  
Joshua Russell ◽  
Matt Kaeberlein
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Large Scale ◽  
Meta Analysis ◽  
Brain Regions ◽  
Data Sets ◽  
Data Types ◽  
C Elegans

Abstract Here we present new computational and experimental methods to leverage the gene expression and neuropathology data collected from several large-scale studies of Alzheimer’s disease . These data sets include diverse data types, including transcriptomics, neuropathology phenotypes such as quantification of amyloid beta plaques and tau tangles in different brain regions, as well as assessments of dementia prior to death. This meta-analysis is a complex undertaking because the available data are from different studies and/or brain regions involving study-specific confounders and/or region-specific biological processes. We have therefore taken neural network and probabilistic computational approaches that reduce the data dimensionality, allowing statistical comparison across all brain samples. These approaches identify gene expression changes that are significantly associated with clinical and neuropathological assessment of Alzheimer’s disease. We then conduct in vivo validation of the genes through genetic screening of C. elegans models of Alzheimer's disease utilizing our automated robotic lifespan analysis platform. This approach allows for the greater leverage of existing Alzheimer’s disease biobank data to identify deep genetic signatures that could help identify new clinical gene-expression markers and pharmacological targets for Alzheimer’s disease.

scholarly journals In Vitro31P NMR Spectroscopy Detects Altered Phospholipid Metabolism in Alzheimer's Disease

1986 ◽  
Vol 13 (S4) ◽  
pp. 535-539 ◽  
Author(s):  
Orietta Miatto ◽  
R. Gilberto Gonzalez ◽  
Ferdinando Buonanno ◽  
John H. Growdon
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nmr Spectroscopy ◽  
Inorganic Phosphorus ◽  
High Energy ◽  
Phospholipid Metabolism ◽  
Neuronal Membrane ◽  
Control Subjects ◽  
And Control

Abstract:In order to study possible metabolic derangements in Alzheimer's disease (AD), we performed phosphorus 31 nuclear magnetic resonance (31P NMR) spectroscopy on brain samples obtained at autopsy from 7 patients with AD and 9 control subjects. Aqueous solutions of brain tissue contained well-defined peaks of intermediate compounds in phospholipid metabolism, including the phosphomonoesters phosphocholine and phosphoethanolamine, and the phosphodiesters glycerophosphorylcholine and glycerophosphorylethanolamine. 3IP NMR spectra also displayed the inorganic phosphorus signal, which provides an index to the in vivo concentration of high-energy compounds.We found evidence for altered phospholipid metabolism in that relative levels of phosphomonoesters were decreased, and phosphodiesters increased, in frontal and parietal regions of patients with AD compared to control subjects. The inorganic phosphorus resonance peaks were similar in AD and control subjects, suggesting that energy stores are not diminished in AD. These preliminary data are consistent with the hypothesis that abnormalities in phospholipid metabolism contribute to possible neuronal membrane dysfunction and impaired cholinergic neurotransmission in AD.

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