Platelets isolated from an Alzheimer mouse damage healthy cortical vessels and cause inflammation in an organotypic ex vivo brain slice model

Platelets are anuclear blood cells and play a major role in hemostasis and thrombosis. Platelets express amyloid-precursor protein (APP), release beta-amyloid (Aβ) and are stimulated (pre-activated) in Alzheimer’s disease (AD). We hypothesize that such stimulated platelets severely damage brain vessels which subsequently leads to cerebrovascular damage in AD. In order to study this issue we isolated platelets from AD mice (expressing APP with the Swedish-Dutch-Iowa mutations), labeled them with the red fluorescent dye PKH26 and transcardially infused these freshly isolated platelets into the brains of anesthetized healthy C57BL6 wildtype mice. Brains were immediately taken, 110 µm thick organotypic brain slices prepared and cultured for 1 or 14 days. We observed that red PKH26(+) fluorescent platelets were localized in collagen IV and Lectin-649 counterstained cortical brain vessels and that platelets from AD mice severely damaged cortical brain vessels in wildtype mice and entered the brain parenchyma. Confocal microscopy showed immunoreactivity for matrix metalloproteinases (MMP-2 and MMP-9) and beta-amyloid around these platelets. The effect was completely inhibited with an MMP inhibitor. Furthermore, isolated AD platelets caused inflammation and activated microglia around the site where platelets damaged cortical brain vessels. We conclude that AD-derived platelets more aggressively damage healthy vessels which may consequently play a role in the progression of cerebral amyloid angiopathy in AD.