Alzheimer's disease and dementia with Lewy bodies: Special focus on the role of serpins

Abstract: Serine protease inhibitors (Serpins) are involved in the pathogenesis of neurodegenerative dementia, including the two most common types, Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). The pathological characteristics of AD include senile plaques, mainly composed of aggregated amyloid-beta peptide (Abeta1-42), but also serpins, and neurofibrillary tangles of hyperphosphorylated tau protein. Pathological hallmarks of DLB include aggregates of alpha-synuclein (Lewy bodies), however, co-existing AD pathology is also frequently found. In the present work, we have investigated the role of three serpins, namely alpha1-antichymyotrypsin, alpha1-antitrypsin and neuroserpin, in the context of AD and DLB. We have shown that alpha1-antichymotrypsin: (i) renders the oligomer formation profile of incubated Abeta1-42, favouring dimer formation; (ii) under certain conditions appears to protect Abeta1-42 from chymotrypsin digestion and;(iii) in combination with soluble forms of Abeta1-42, significantly affects the global gene expression of primary fetal human astrocytes; (iv) can influence binding and, potentially, uptake of aggregated Abeta1-42 in primary adult human astrocytes. In two clinical studies we have: (i) for the first time, determined cerebrospinal fluid levels of neuroserpin and established a link to AD as significantly higher levels of neuroserpin were found in AD patients than in non-demented controls and DLB patients; (ii) showed that higher levels of cerebrospinal fluid alpha1-antitrypsin and plasma alpha1-antichymotrypsin correlate to lower cognitive function in patients with DLB and AD, respectively; (iii) showed that patients with AD and DLB have higher levels of intercellular adhesion molecule-1 and platelet endothelial cell adhesion molecule-1. Our findings support the statement that inflammatory and vascular mechanisms are involved in dementia pathogenesis and suggest that serpins most likely are involved in the processes leading to cognitive dysfunction. Further research is needed to assess the distinct actions of serpins in the mechanisms leading to neurodegeneration and dementia.