Neuropathological changes in scrapie and Alzheimer's disease are associated with increased expression of apolipoprotein E and cathepsin D in astrocytes

Abstract

With the rationale that the neuropathological similarities between scrapie and Alzheimer's disease reflect convergent pathological mechanisms involving altered gene expression, we set out to identify molecular events involved in both processes, using scrapie as a model to study the time course of these changes. We differentially screened a cDNA library constructed from scrapie-infected mice to identify mRNAs that increase or decrease during disease and discovered in this way two mRNAs that are increased in scrapie and Alzheimer's disease. These mRNAs were subsequently shown by sequence analysis to encode apolipoprotein E and cathepsin D (EC 3.4.23.5). Using in situ hybridization and immunocytochemistry to define the cellular and anatomic pathology of altered gene expression, we found that in both diseases the increase in apolipoprotein E and cathepsin D mRNAs and proteins occurred in activated astrocytes. Iit scrapie, the increase in gene expression occurred soon after the amyloid-forming abnormal isoform of the prion protein has been shown to accumulate in astrocytes. In Alzheimer's disease, the increased expression of cathepsin D also occurred in association with ,-amyloid. These studies reveal some of the molecular antecedents of neuropathological changes in scrapie and Alzheiner's disease and accord new prominence to the role of astrocytes in neurodegenerative conditions.

Improvement of neuronal cell survival by astrocyte‐derived exosomes under hypoxic and ischemic conditions depends on prion protein

“…Apolipoprotein E is involved in neural repair and contributes to neuronal survival (Beffert et al, 2006;Gutman et al, 1997;Poirier et al, 1991). Moreover, increased expression of apolipoprotein E and immunohistological co-localization of apolipoprotein E and PrP have been described in animal models of transmissible spongiform encephalopathies (Diedrich et al, 1991;Hochstrasser et al, 1997;Nakamura et al, 2000), suggesting that apolipoprotein E is involved in the pathogenesis of prion diseases. Similarly, enhanced clusterin/apolipoprotein J levels have been found in prion-related encephalopathies.…”

Monoamine oxidase‐B in astrocytes

“…In the present study we failed to determine astrocyte subtypes with phase-contrast microscopy of autoradiographs in cell culture dishes due to poor resolution. Various biochemical changes have been shown to occur in association with reactive astrocytosis (Diedrich et al, 1991;Schwarcz, 1992;Tanaka et al, 1991) and such changes may lead to substantial alterations in regional metabolism. It is generally regarded that gliotic alterations appear secondarily to other processes causing neuronal cell death; yet, several recent works suggest a role of the astroglial reaction as a pathogenetic mechanism in neuronal degeneration (for review see Frederickson, 1992).…”

Apolipoproteins in the brain: implications for neurological and psychiatric disorders

“…There is no exchange of brain-derived and peripheral ApoE; therefore, the CNS represents a distinct compartment in terms of ApoE metabolism [19]. Astrocytes are the primary source of ApoE in the brain; however, ApoE is also expressed by oligodendrocytes, ependymal layer cells, microglia and, under certain physiological circumstances, in neurons [33][34][35][36][37][38][39][40][41]. The upstream promoter region of the APOE gene contains several regulatory regions that can bind a variety of different transcription factors (TFs) [42][43][44][45][46][47][48][49].…”