A new treatment target for Alzheimer’s

A recent study published in the journal Nature reported the co-aggregation of medin, a fragment of lactadherin, with vascular amyloid-β in Alzheimer’s disease (AD).

Amyloidosis is caused by systemic or local accumulation of misfolded, insoluble, and aggregated proteins. So far, 36 amyloids have been identified, and many are associated with tissue dysfunction and neurodegenerative diseases. Medin, a 50-amino acid peptide cleaved from milk-fat globule EGF-like factor 8 (MFG-E8), also known as lactadherin, is the most common human amyloid. Prior studies indicate that medin aggregates may result in arterial wall degeneration and cause arterial stiffening and cerebrovascular dysfunction.

Study: Medin co-aggregates with vascular amyloid-β in Alzheimer’s disease. Image Credit: PopTika / ShutterstockStudy: Medin co-aggregates with vascular amyloid-β in Alzheimer’s disease. Image Credit: PopTika / Shutterstock

The study and findings

In the present study, researchers analyzed the role of medin in postmortem human brain tissue and mouse models of cerebral β-amyloidosis. First, brain tissue from two amyloid-β precursor protein (APP) transgenic mouse lines (APP23 and APPPS1) was stained using a polyclonal antibody against MFG-E8. This revealed extensive co-localization with amyloid plaques in both models.

Amyloid staining was absent after the genetic elimination of medin by cross-breeding APP transgenic lines with mice knocked out of medin-containing C2 domain of Mfge8 (Mfge8 C2 KO); punctate staining in astrocytes was still visible. In addition, there was co-localization of MFG-E8 staining with cerebral β-amyloid angiopathy (CAA), i.e., vascular deposits of amyloid-β.

Vascular MFG-E8 staining was evident in APP23 mice but not in APPPS1 mice or APP23 mice crossed with the Mfge8 C2 KO line. Next, the team determined the role of medin and MFG-E8 in β-amyloidosis by quantifying plaque and CAA load. The lack of extracellular medin or MFG-E8 in Mfge8 C2 KO mice resulted in a significant reduction in plaque deposition at the early stages of pathology in both mouse lines.

Nonetheless, parenchymal plaque load was not distinguishable at later states in both models. Mfge8 C2 KO mice showed an 85% reduction in CAA burden compared to Mfge8 wild-type mice in the APP23 model. Further investigations indicated a high enrichment of MFG-E8 in the vasculature that was further enhanced with CAA.

Additionally, the researchers examined autopsied frontal and occipital brain tissues from 16 AD patients by immunostaining. Staining brain sections with an antibody against full-length MFG-E8 revealed some localized vascular immunoreactivity. Contrastingly, anti-medin staining resulted in widespread immunoreactivity in cerebral vasculature on aggregate-like structures, but amyloid plaques were not detectably labeled.

Next, cerebral blood vessels from the occipital cortex were isolated from controls and AD patients with mild, severe, or no CAA. MFG-E8 protein levels were up to 40 times increased in cerebral vasculature relative to total brain homogenates. Moreover, MFG-E8 protein levels were 2.3-fold elevated in the blood vessels of AD patients with severe CAA relative to those with mild or no CAA.

The researchers also observed a positive correlation of MFG-E8 levels with the Aβ40-to-Aβ42 ratio and total amyloid-β levels in blood vessels. They also examined MFG-E8 and medin levels in total brain homogenates and vascular fractions from six sex- and age-matched individuals using western blotting.

Detection with anti-medin antibody confirmed the increased MFG-E8 levels in all fractions in AD patients with severe CAA relative to controls and AD patients with mild CAA. Moreover, higher fragmentation of MFG-E8 was observed in the vascular fraction of only AD patients with severe CAA, implying the presence of medin aggregates.

Besides, the researchers assessed the expression of the MFGE8 gene in the dorsolateral prefrontal cortex from 566 patients in the Religious Orders Study/Memory and Aging Project (ROSMAP) cohort. MFGE8 expression was significantly elevated in AD patients (from the cohort) relative to controls without dementia

Notably, higher MFGE8 expression was significantly associated with elevated measures of cognitive decline independent of plaque or tau pathology. The team used immune-electron microscopy to examine the subcellular localization of MFG-E8 and medin around amyloid-β plaques in APP transgenic mouse lines.

Immunolabeling of amyloid fibrils was conspicuous in APPPS1 x Mfge8 wild-type mice but not in the APPPS1 x Mfge8 C2 KO mice. Moreover, amyloid plaques had less pronounced fibrils in the Mfge8 wild-type mice than in Mfge8 C2 KO mice. The authors found that recombinant amyloid-β (Aβ40) and medin co-aggregate in vitro.

Of note, medin aggregated faster than Aβ40, whereas a mix of both aggregated at the same rate as medin. Furthermore, modified peptides – C-terminus of medin (CT-medin) and methionine Aβ42 (Met-Aβ) – with slower aggregation kinetics were used to examine their interaction in vitro. The two modified peptides readily co-aggregated with slower kinetics than individually.

Notably, pre-formed aggregates (seeds) of either peptide accelerated the aggregation of homologous and heterologous peptides. Finally, the team investigated whether medin aggregates could seed amyloid-β aggregation in vivo. To this end, they injected brain extract from an end-stage APP23 transgenic mouse or medin-containing human aorta-derived material into the hippocampus of mice.

Mouse brain extract injection caused overt amyloid-β deposition six months later, whereas endogenous amyloid-β deposition was absent in age-matched control mice. Similarly, injection of human aortic extracts containing medin induced significant premature amyloid-β aggregation six months later. Depleting medin from the aortic extract completely abolished amyloid-β aggregation.


To summarize, the study demonstrated in vitro co-aggregation of medin and amyloid-β, in vitro and in vivo cross-seeding of amyloid-β aggregation by medin, and lower CAA burden in the absence of medin in mouse models. Together, the findings suggested that interactions between amyloid-β and medin promote amyloid-β aggregation and that targeting medin might offer a therapeutic solution to preserving brain function by improving vascular health.\

#treatment #target #Alzheimers
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