SERPINA3 in glioblastoma and Alz h eimer's dis e as e

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Although GBM can arise at any age, incidence increases with aging and the median age of diagnosis is 64 years. Aging-induced changes in gene expression and immune microenvironment contribute to the increase of GBM incidence and mortality in elderly patients [1]. An age-related factor that has been previously implicated in neurological aging and may contribute to increased glioma incidence is upregulation of SERPINA3. Increased SERPINA3 levels, glial-derived or otherwise, have been linked to altered brain function in aging and implicated in the development of brain amyloidosis in Alzheimer's disease (AD). AD patients and animal models show a prominent cellular SERPINA3 expression in the vicinity amyloid plaques and increased levels of extracellular SERPINA3 in direct contact with the amyloid beta (AP) aggregates [2]. Additionally, transgenic induction of SERPINA3 overexpression in astroglia resulted in increased brain AP burden presumptively by interfering with AP aggregation or degradation and clearance of amyloid aggregates [3]. Accordingly, constitutive loss of SERPINA3 led to a decrease in brain AP deposition in AD transgenic mice, an effect that was synergistically enhanced in mice lacking both SERPINA3 and apolipoprotein E [2, 4]. Moreover, increased level of circulating SERPINA3 is correlated with the presence of brain microbleeds and white matter hyperintensities in elderly patients [5]. This indicates peripherally derived SERPINA3 is able to affect the brain directly, after crossing the blood brain barrier, or indirectly, by affecting the cellular response at border tissues like the meninges.