Altered expression of apolipoprotein E, amyloid precursor protein and presenilin-1 is associated with chronic reactive gliosis in rat cortical tissue

A major characteristic feature of Alzheimer's disease is the formation of c ompact, extracellular deposits of beta -amyloid (senile plaques). These dep osits are surrounded by reactive astrocytes, microglia and dystrophic neuri tes. Mutations in three genes have been implicated in early-onset familial Alzheimer's disease, However, inflammatory changes and astrogliosis are als o believed to play a role in Alzheimer's pathology. What is unclear is the extent to which these factors initiate or contribute to the disease progres sion. Previous rat studies demonstrated that heterotopic transplantation of foetal cortical tissue onto the midbrain of neonatal hosts resulted in sus tained glial reactivity for many months. Similar changes were not seen in c ortex-to-cortex grafts. Using this model of chronic cortical gliosis, we ha ve now measured reactive changes in the levels of the key Alzheimer's disea se proteins. namely the amyloid precursor protein, apolipoprotein E and pre senilin-1. These changes were visualised immunohistochemically and were qua ntified by western blot analysis. We report here that chronic cortical glio sis in the rat results in a sustained increase in the levels ci apolipoprot ein E and total amyloid precursor protein. Reactive astrocytes in heterotop ic cortical grafts were immunopositive for both of these proteins. Using a panel of amyloid precursor protein antibodies we demonstrate that chronic r eactive gliosis is associated with alternative cleavage of the peptide. No significant changes in apolipoprotein E or amyloid precursor protein expres sion were seen in non-gliotic cortex-to-cortex transplants. Compared to hos t cortex, the levels of both N-terminal and C-terminal fragments of preseni lin-1 were significantly lower in gliotic heterotopic grafts, The changes described here largely mirror those seen in the cerebral cortex of humans with Alzheimer's disease and are consistent with the proposal th at astrogliosis may be an important factor in the pathogenesis of this dise ase. (C) 2001 IBRO. Published by Elsevier Science Ltd, All rights reserved.