Microtubule destabilization leads to APP phosphorylation and processing: Implications for Alzheimer's disease pathogenesis

Abstract

However, also prion proteins produced by neurons, can form amyloid plaques in the brain. In variant Creutzfeldt Jakob disease (vCJD), sporadic CJD forms with a longer duration, hereditary CJD and Gerstmann Straussler Scheinker’s disease (GSS) prion amyloid plaques can be found. In the present immunohistochemical study we investigated the presence of amyloid associated proteins such as complement and alpha1-antichymotrypsin (ACT), microglia (HLADR), ubiquitin and tau in 4 different forms of prion diseases with prion amyloid plaques with or without prion cerebral amyloid angiopathy (CAA) and compared the results with the findings in classical AD. Methods: Cortical tissue obtained at autopsy was used from 3 vCJD (16, 37 and 49 y old), 2 sporadic CJD patients with longer duration (MM2, VV2 forms; resp. 55 y and 58 y) and 3 different GSS patients (57y, 57y, 45y) including 2 novel prion mutations, i.e. Y226X and Q227X stop codon mutations, and 5 AD cases (29y 76y). Immunohistochemistry was performed on formalin fixed tissue using antibodies against Abeta 1-17, prion proteins (3F4), complement C3b, HLADR, ubiquitin and Tau (AT8) and some sections were counterstained with Congo red. Cryostat sections were used for staining with antibodies against complement C3c and ACT. Results: Complement proteins were found in amyloid deposits both in AD and in prion diseases without Abeta. In a case with extensive prion CAA, complement was also detected in the amyloidotic vessel wall. Clustering of microglia was seen both in AD plaques and around prion plaques but also around prion CAA. Extensive neurofibrillary degeneration with numerous tangles throughout the cortex was found in the stopcodon Q227X patient (aged 45y) mimicking the AD cases. In the MM2 prion case (55 y) tau and ubiquitin was found especially near prion plaques. Prion CAA showed a mild tau and ubiquitin positivity around the vessel walls. No tau was found in the vCJD cases. Conclusions: Inflammatory changes and neurofibrillary degeneration seems to be related to cerebral amyloidosis irrespective the type of amyloid.