Abstract
Brain accumulation of amyloid-beta (Aβ) is a crucial feature in Alzheimer´s disease (AD) and cerebral amyloid angiopathy (CAA), although the pathophysiological relationship between these diseases remains unclear. Numerous proteins are associated with Aβ deposited in parenchymal plaques and/or cerebral vessels. We hypothesized that the study of these proteins would increase our understanding of the overlap and biological differences between these two pathologies and may yield new diagnostic tools and specific therapeutic targets. We used a laser capture microdissection approach combined with mass spectrometry in the APP23 transgenic mouse model of cerebral-β-amyloidosis to specifically identify vascular Aβ-associated proteins. We focused on one of the main proteins detected in the Aβ-affected cerebrovasculature: MFG-E8 (milk fat globule-EGF factor 8), also known as lactadherin. We first validated the presence of MFG-E8 in mouse and human brains. Immunofluorescence and immunoblotting studies revealed that MFG-E8 brain levels were higher in APP23 mice than in WT mice. Furthermore, MFG-E8 was strongly detected in Aβ-positive vessels in human postmortem CAA brains, whereas MFG-E8 was not present in parenchymal Aβ deposits. Levels of MFG-E8 were additionally analysed in serum and cerebrospinal fluid (CSF) from patients diagnosed with CAA, patients with AD and control subjects. Whereas no differences were found in MFG-E8 serum levels between groups, MFG-E8 concentration was significantly lower in the CSF of CAA patients compared to controls and AD patients. Finally, in human vascular smooth muscle cells MFG-E8 was protective against the toxic effects of the treatment with the Aβ40 peptide containing the Dutch mutation. In summary, our study shows that MFG-E8 is highly associated with CAA pathology and highlights MFG-E8 as a new CSF biomarker that could potentially be used to differentiate cerebrovascular Aβ pathology from parenchymal Aβ deposition.
Highlights
Cerebral β-amyloidosis is characterized by the accumulation of amyloid-beta (Aβ) protein in the brain parenchyma and cerebral blood vessels, which are major features of Alzheimer’s disease (AD) and Aβ-associated cerebral amyloid angiopathy (CAA), respectively [1, 2]
We focused our study on milk fat globule-EGF factor 8 (MFG-E8), as it was one of the proteins detected with Aβ-affected cerebral vessels and absent from parenchymal Aβ plaques in the APP23 mouse model of AD/CAA
After exclusion of the proteins identified in parenchymal plaques from APP23 brains and in brain vessels from WT mice, the only proteins exclusively detected in the Aβ-affected cerebral vasculature were MFG-E8 and tissue inhibitor of metalloproteinases‐3 (TIMP3) (Additional file 3)
Summary
Cerebral β-amyloidosis is characterized by the accumulation of amyloid-beta (Aβ) protein in the brain parenchyma and cerebral blood vessels, which are major features of Alzheimer’s disease (AD) and Aβ-associated cerebral amyloid angiopathy (CAA), respectively [1, 2]. AD is the main cause of dementia [3], whereas CAA is the most common cause of lobar intracerebral haemorrhage (ICH) in elderly individuals [4, 5]. Population-based autopsy studies have estimated a CAA prevalence of 20–40% in non-demented individuals and 50–60% in those with dementia, which demonstrates its strong association with AD [8]. The prevalence of CAA pathology is high in patients with AD, accounting for 47–100% of those patients [8]
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