Molecular abnormalities in autopsied brain tissue from the inferior horn of the lateral ventricles of nonagenarians and Alzheimer disease patients

Abstract

Background: The ventricular system plays a vital role in blood-cerebrospinal fluid (CSF) exchange and interstitial fluid-CSF drainage pathways. CSF is formed in the specialized secretory tissue called the choroid plexus, which consists of epithelial cells, fenestrated capillaries and the highly vascularized stroma. Very little is currently known about the role played by the ventricles and the choroid plexus tissue in aging and Alzheimer's disease (AD). Methods: In this study, we used our state-of-the-art proteomic platform, a liquid chromatography/mass spectrometry (LC-MS/MS) approach coupled with Tandem Mass Tag isobaric labeling to conduct a detailed unbiased proteomic analyses of autopsied tissue isolated from the walls of the inferior horn of the lateral ventricles in AD (77.2 ± 0.6 yrs), age-matched controls (77.0 ± 0.5 yrs), and nonagenarian cases (93.2 ± 1.1 yrs). Results: Ingenuity pathway analyses identified phagosome maturation, impaired tight-junction signaling, and glucose/mannose metabolism as top significantly regulated pathways in controls vs nonagenarians. In matchedcontrol vs AD cases we identified alterations in mitochondrial bioenergetics, oxidative stress, remodeling of epithelia adherens junction, macrophage recruitment and phagocytosis, and cytoskeletal dynamics. Nonagenarian vs AD cases demonstrated augmentation of oxidative stress, changes in gluconeogenesis-glycolysis pathways, and cellular effects of choroidal smooth muscle cell vasodilation. Amyloid plaque score uniquely correlated with remodeling of epithelial adherens junctions, Fc γ-receptor mediated phagocytosis, and alterations in RhoA signaling. Braak staging was uniquely correlated with altered iron homeostasis, superoxide radical degradation and phagosome maturation. Conclusions: These changes provide novel insights to explain the compromise to the physiological properties and function of the ventricles/choroid plexus system in nonagenarian aging and AD pathogenesis. The pathways identified could provide new targets for therapeutic strategies to mitigate the divergent path towards AD.

Pathogenesis of Alzheimer’s disease: Involvement of the Choroid Plexus

“…3a, b). These findings indicated the involvement of the ChP as well as of other structures 34 in the CSF All rights reserved. No reuse allowed without permission.…”

APOE genotype dependent molecular abnormalities in the cerebrovasculature of Alzheimer’s disease and age-matched non-demented brains

“…Xcalibur (Thermo) software was used to control the instrument in data dependent acquisition (DDA) mode. DDA settings for these MS experiments followed our previous work [57,61], and were as follows: full-scan MS resolution = 140 000 full width at half maximum at 200 m/z, full-scan range = 380-1250 m/z, isolation width = 1.2 m/z, higher energy C-trap dissociation relative collision energy = 29, a minimum m/z setting of 100 m/z was used for all MS 2 spectra, MS 2 resolution = 35,000, dynamic exclusion = 180 s, and a Top 15 high/low duty cycle was used for precursor ion selection. Sample limitations did not allow for extensive two-dimensional (2D) fractionation of the labeled peptides, therefore we the use of a narrow isolation window and an ultra-long shotgun gradient was used to minimize the deleterious effects on quantitative accuracy that typically result from co-isolation of isobaric precursors.…”

“…Unbiased proteomic analysis is an extremely powerful tool which can provide a very expansive interrogation of the molecular response in neurodegenerative diseases [50][51][52][53] and can lead to the identification of pathogenic mechanisms and novel molecular targets [54][55][56] for therapeutic exploration. Herein, we have utilized a novel protein extraction protocol, separating isolated cerebrovessels into cytosolic, membrane and nuclear fractions to increase the depth of the protein mining process, and coupled this with a 10-plex tandem isobaric mass tag (TMT) approach for interrogation with an ultra-high pressure liquid chromatography MS/MS (Q-Exactive) method [57]. In this study, we have detailed the unique molecular profiles and pathogenic mechanisms driven by APOE variant genotypes in cerebrovessels of the inferior frontal gyrus of AD and control patients.…”

Neuroprotective Effect of SGLT2 Inhibitors

“…There is in vivo evidence for the expression of SGLT2 protein in choroid plexus epithelial cells and ependymal cells of the human brain [ 56 ]. This is crucial information indicating that SGLT2 may have an influence on the composition of the cerebrospinal fluid (CSF), whose role in the pathology of neurodegenerative disorders provides a new direction for research and requires further investigation [ 57 ].…”