NEURON-SELECTIVE GAMMA-SECRETASE INTERACTIONS WITH PROTEINS EXPRESSED IN HUMAN BRAIN

Abstract

Background:Alzheimer’s disease (AD) is characterized by the presence of amyloid beta (Ab) plaques and neurofibrillary tangles (NFT). SPPL2b is a novel enzyme that can process TNFa and BRI2, substrates involved in Ab plaque and NFT formation. Since changes in BRI2 and TNFa were previously identified in early stages of AD, we have now extensively characterized SPPL2b in human brain tissue from controls and AD patients at different stages of the disease. We also investigated the relation of SPPL2b with important pathological AD hallmarks including amyloid plaques, NFTs, ER stress and ubiquitin. Methods: SPPL2b expression levels were quantified in post-mortem human homogenates from AD patients (n1⁄414) and controls (n1⁄413) by western blot. SPPL2b immunostaining was evaluated on paraffin sections from AD patients (n 1⁄4 12) and age-matched controls (n1⁄415). Results: SPPL2b levels were 10-fold increased (p < 0.0001) in AD hippocampus compared to non-demented controls. SPPL2b was strongly correlated (r 1⁄4 0.785, p < 0.0001) to Braak stages showing a significant increased from Braak III to IV, stages in which cognitive impairment starts. Strong SPPL2b immunoreactivity in the hippocampus was observed in early AD stages (p <0 .0001), which was associated with both NFT and Ab plaques. Preincubation and comparison of staining patterns of SPPL2b family members proved that the observations were SPPL2b-specific. Conclusions: We found a dramatically increase of SPPL2b in early stages of AD. SPPL2b processes BRI2 and TNF a, proteins involved not only in Ab homeostasis but also in chronic inflammation and NFT formation. These data reveal a novel potential AD etiological factor that links Ab plaques and NFT and thus forms a new and promising target for disease modifying therapies.