Pathological changes in basement membranes and dermal connective tissue of skin from patients with hereditary cystatin C amyloid angiopathy

Abstract

Hereditary cystatin C amyloid angiopathy (HCCAA) is a genetic disease caused by a mutation in the cystatin C gene. Cystatin C is abundant in cerebrospinal fluid and the most prominent pathology in HCCAA is cerebral amyloid angiopathy due to mutant cystatin C amyloid deposition with associated cerebral hemorrhages, typically in young adult carriers. Analyses of post-mortem brain samples shows that pathological changes are limited to arteries and regions adjacent to arteries. The severity of pathological changes at post-mortem has precluded the elucidation of the evolution of histological changes. Mutant cystatin C deposition in carriers is systemic and has, for example, been described in the skin, suggesting similar pathological mechanisms both in the brain and outside of the central nervous system. The aim of this study was to use skin biopsies from asymptomatic and symptomatic carriers to study intermediate events in HCCAA pathogenesis. We found that cystatin C deposition in minimally affected samples was limited to the basement membrane (BM) between the dermis and epidermis. When the deposits were more advanced, they extended to other BM regions in the skin. Our results showed that the immunoreactivity of the BM protein COLIV was increased to a similar extent in all carrier biopsies and cystatin C deposits were in close association with COLIV. The density of fibroblasts in the upper dermis of carrier skin was increased, whereas the distribution of other cell types examined did not differ compared with control biopsies. COLIV and cystatin C immunoreactivity in carrier biopsies was closely associated with the fibroblasts. The results of this study, in conjunction with our previous results regarding pathological BM changes in leptomeningeal arteries of patients, suggest that BM changes are early and important events in HCCAA pathogenesis that could facilitate cystatin C deposition and aggregation.

Clearance of interstitial fluid (ISF) and CSF (CLIC) group—part of Vascular Professional Interest Area (PIA)

“…In addition, non‐human primate models are known to develop extensive CAA thus offering potential preclinical avenues for investigation, especially in the context of white matter lesions 33,34 . Intramural accumulation of cystatin amyloid aggregates in Icelandic CAA are also observed in skin vessels, suggesting that in vitro models of this disorder could provide convenient platforms to study mechanistic properties of affected vessels 35 …”

“…The yellow line passing along the IPAD pathway shows how CSF that has entered the ISF of the brain also drains from the brain along IPAD pathways in artery walls. SMCs in the tunica media of arteries supply the models of this disorder could provide convenient platforms to study mechanistic properties of affected vessels 35.…”

Did ketogenic diet in past centuries protect against the consequence of the cystatin L68Q mutation in carriers of HCCAA?

“…Haegt er að kanna ástand uppsöfnunar á cystatin C í húð arfbera með því að ónaemislita fyrir cystatin C uppsöfnun í stungusýni úr húð þeirra. 6 Vegna nýrrar vitneskju var athyglisvert að kanna hvort glútathíon gaeti mögulega tengst breytingum í faeðu á 19. öld. Aðferðir Í byrjun 19. aldar var mataraeði Íslendinga mjög einhaeft.…”

“…3 Þar sem cystatin C temprar virkni TGFb vaxtarþáttar með því að bindast viðtaka þess (TGFbRII) 14 gaeti laekkun á cystatin Cmagni valdið þeirri auknu bandvefsuppsöfn un sem sést í heilaaeðum og húð arfbera. 4,6 Önnur afleiðing af of virkum TGFbvaxtarþaetti er laekkun glútathíons. 15,16 Á hinn bóg inn minnkar glútathíon bandvefsuppsöfnun af völdum TGFb og Smad3 15,17 (mynd 7).…”