Amyloid-β deposition in the cerebral cortex in Dementia with Lewy bodies is accompanied by a relative increase in AβPP mRNA isoforms containing the Kunitz protease inhibitor

Abstract

Deposition of amyloid-β, the fibrillogenic product of the cell surface protein AβPP (amyloid-β protein precursor), occurs in the cerebral cortex of patients with Dementia with Lewy bodies (DLB). Amyloid deposition, basically in the form of senile plaques, occurs not only in the common form (DLBc), which is defined by changes consistent with diffuse Lewy body disease accompanied by Alzheimer's disease (AD), but also in the pure form (DLBp), in which neurofibrillary tangles are absent. The present study analyses the expression of AβPP mRNA isoforms with (AβPP751 and AβPP770) and without (AβPP695) the Kunitz-type serine protease inhibitor (KPI) domain, in the cerebral cortex in DLBc ( n = 4), DLBp ( n = 4), Parkinson's disease (PD, n = 5), AD ( n = 3 stages I–IIA, and n = 4 stage VC of Braak and Braak), amyloid angiopathy (AA, n = 2) and progressive supranuclear palsy (PSP, n = 4) compared with age-matched controls ( n = 6). For this purpose, TaqMan RT-PCR assay was used on frozen post-mortem samples of the frontal cortex (area 8) obtained with short post-mortem delays (8.29 ± 4.57 h) and strict RNA preservation (A 260/280 of 1.78 ± 0.15). A 3.66-fold, 6.67-fold, 4.28-fold and 5.24-fold increases, in the (AβPP751 + AβPP770)/AβPP695 mRNA ratio were found in DLBc, DLBp, AD stage VC and AA, respectively, when compared with controls. No modifications in the ratio were found in PD, AD stage I–IIA and PSP. These findings suggest that alternative splicing of the AβPP mRNA may play a role in βA4 amyloidogenesis in DLBp, DLBc, AD stage VC and Amyloid angiopathy.