Medin co-aggregates with vascular amyloid-β in Alzheimer’s disease

Abstract

Aggregates of medin amyloid (a fragment of the protein MFG-E8, also known as lactadherin) are found in the vasculature of almost all humans over 50 years of age1,2, making it the most common amyloid currently known. We recently reported that medin also aggregates in blood vessels of ageing wild-type mice, causing cerebrovascular dysfunction3. Here we demonstrate in amyloid-β precursor protein (APP) transgenic mice and in patients with Alzheimer’s disease that medin co-localizes with vascular amyloid-β deposits, and that in mice, medin deficiency reduces vascular amyloid-β deposition by half. Moreover, in both the mouse and human brain, MFG-E8 is highly enriched in the vasculature and both MFG-E8 and medin levels increase with the severity of vascular amyloid-β burden. Additionally, analysing data from 566 individuals in the ROSMAP cohort, we find that patients with Alzheimer’s disease have higher MFGE8 expression levels, which are attributable to vascular cells and are associated with increased measures of cognitive decline, independent of plaque and tau pathology. Mechanistically, we demonstrate that medin interacts directly with amyloid-β to promote its aggregation, as medin forms heterologous fibrils with amyloid-β, affects amyloid-β fibril structure, and cross-seeds amyloid-β aggregation both in vitro and in vivo. Thus, medin could be a therapeutic target for prevention of vascular damage and cognitive decline resulting from amyloid-β deposition in the blood vessels of the brain.

Spatial epigenome–transcriptome co-profiling of mammalian tissues

“…We performed spatial ATAC–RNA-seq on adult (31-year-old male) human brain hippocampal formation, which is a complex brain region involved in cognitive functions and diseases such as major depression disease 40 and Alzheimer’s disease 41 . We identified seven and eight major clusters for ATAC and RNA, respectively, and the spatial pattern agreed with major anatomical landmarks (Fig.…”

Viruses and amyloids - a vicious liaison

“…Cerebral amyloid angiopathy (CAA) is a prevalent pathology in amyloidosis. Eight amyloid proteins, Aβ, ATTR, ADan, ABri, ACys, APrP, AGel, AMed [ 159 , 160 ] ( Table 1 ), are known to form amyloid in CAA and can cause vascular dementia. These vascular deposits are associated with accumulation of ApoE, Serum amyloid p component (SAP) and glycosaminoglycans (GAGs) which are amyloid associated proteins and glycans [ 161 ] which together severely impairs the vasculature increasing the risk for haemorrhagic stroke.…”

New Pathways Identify Novel Drug Targets for the Prevention and Treatment of Alzheimer’s Disease

“…On the contrary, medin, a known protein, promotes the formation of amyloid aggregates and deposits by coaggregation with Aβ. Researchers hope that medin inhibitors could block the formation of amyloid deposits and may behave as anti-amyloid agents [ 133 ]. It has been published very recently that 14-3-3 proteins also bind amyloids, and thus, they can also be targeted as an anti-aggregation approach [ 134 ].…”