Proteomics analysis identifies new markers associated with capillary cerebral amyloid angiopathy in Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is characterized by amyloid beta (Aβ) deposits as plaques in the parenchyma and in the walls of cortical and leptomeningeal blood vessels of the brain called cerebral amyloid angiopathy (CAA). It is suggested that CAA type-1, which refers to amyloid deposition in both capillaries and larger vessels, adds to the symptomatic manifestation of AD and correlates with disease severity. Currently, CAA cannot be diagnosed pre-mortem and disease mechanisms involved in CAA are elusive. To obtain insight in the disease mechanism of CAA and to identify marker proteins specifically associated with CAA we performed a laser dissection microscopy assisted mass spectrometry analysis of post-mortem human brain tissue of (I) AD cases with only amyloid deposits in the brain parenchyma and no vascular related amyloid, (II) AD cases with severe CAA type-1 and no or low numbers of parenchymal amyloid deposits and (III) cognitively healthy controls without amyloid deposits. By contrasting the quantitative proteomics data between the three groups, 29 potential CAA-selective proteins were identified. A selection of these proteins was analysed by immunoblotting and immunohistochemistry to confirm regulation and to determine protein localization and their relation to brain pathology. In addition, specificity of these markers in relation to other small vessel diseases including prion CAA, CADASIL, CARASAL and hypertension related small vessel disease was assessed using immunohistochemistry.Increased levels of clusterin (CLU), apolipoprotein E (APOE) and serum amyloid P-component (APCS) were observed in AD cases with CAA. In addition, we identified norrin (NDP) and collagen alpha-2(VI) (COL6A2) as highly selective markers that are clearly present in CAA yet virtually absent in relation to parenchymal amyloid plaque pathology. NDP showed the highest specificity to CAA when compared to other small vessel diseases. The specific changes in the proteome of CAA provide new insight in the pathogenesis and yields valuable selective biomarkers for the diagnosis of CAA.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0540-2) contains supplementary material, which is available to authorized users.

Proteomics of neurodegenerative diseases: analysis of human post‐mortem brain

“…To examine the pathological differences of Aβ deposition in parenchyma and those related to the vasculature, Hondius and colleagues performed a discovery proteomics analysis on laser capture microdissected tissues of the occipital tissues from six cases of healthy controls without any Aβ or tau pathologies, seven cases of AD with severe plaque pathology but no vascular deposits, and seven cases of AD with severe CAA‐type 1 pathology and a negligible amount of plaque pathology (Hondius et al . ). The occipital lobe was chosen because it is the brain region most heavily affected with CAA pathology.…”

“…Recent studies reported the quantification of 2000 or more proteins, and in most cases provided sufficient details to reveal the major alteration of molecular pathways in the disease‐affected brain (e.g., Hondius et al . , ) and others, see below sections for detailed description).…”

Roles of Sorcin in Drug Resistance in Cancer: One Protein, Many Mechanisms, for a Novel Potential Anticancer Drug Target

“…Overexpression in neurodegenerative diseases [31,[36][37][38][39][40][41][42][43][44][45][46][47][48]…”

“…The capability to modulate calcium homeostasis makes sorcin a possible player in brain functions and dysfunctions. Moreover, it is highly expressed in brain pathological conditions, e.g., in brains from Alzheimer's disease (AD) patients vs. controls [37,38], in the frontal cortex of asymptomatic AD patients with respect to symptomatic AD patients [39], in amyloid plaques in sporadic vs. rapidly progressive AD patients, and in AD vs. cerebral amyloid angiopathy patients [40,41], thereby possibly protecting from acceleration progression that takes place in aggressive forms of the disease. Sorcin sequestration by aberrant forms of tau results in impaired calcium homeostasis and resistance to ER stress and may contribute to AD progression [31].…”

Knockout of apolipoprotein A‐I decreases parenchymal and vascular β‐amyloid pathology in the Tg2576 mouse model of Alzheimer's disease

“…Plasma levels of clusterin are higher in individuals with mild cognitive impairment and AD than in age‐matched controls and the rate of cognitive decline is faster in AD patients with elevated levels of clusterin . Clusterin colocalizes with Aβ and is most highly expressed in brain areas with high Aβ pathology and in Aβ‐positive blood vessels, termed cerebral amyloid angiopathy (CAA) . Paradoxically, high levels of clusterin have been shown to prevent Aβ aggregation and promote increased clearance of Aβ from the brain via LRP‐2 .…”