Alzheimer's disease and prion proteins: A meeting made in muscle

One fascinating feature of science is unpredictability. Novel approaches to longstanding and difficult problems can be found unexpectedly in the most unlikely locales. The hallmark of Alzheimer disease (AD) is the selective presence and accumulation in the brain of several abnormal proteins. One of these proteins is amyloid ( protein (AP), a 39 to 43-residue peptide that results from the metabolic breakdown of a larger 3 protein precursor (OPP). Extracellular deposition of AP3 in the form of insoluble filamentous aggregates in the brain parenchyma leads to the formation of the amyloid plaques, a primary lesion of AD.1' 2 Another protein that accumulates inside neurons to form twisted filaments, called paired helical filaments (PHFs), is a phosphorylated form of T, a microtubuleassociated protein that normally promotes microtubule assembly. PHFs form bundles, the neurofibrillary tangles (NFTs), which may lead to neuronal degeneration.3 Over the years, the concomitant presence of these two proteins has puzzled investigators.4 While formation of AP deposits in amyloid plaques is specific to AD and to conditions strictly related to AD such as the sporadic and hereditary forms of cerebral hemorrhage with amyloidosis,5 NFTs can be observed in a variety of conditions including viral infections, neoplasms, and neurodegenerative diseases other than AD.6,7 The chicken-or-egg question has been raised endlessly concerning the relationship of AP3 and abnormal T and of the two corresponding lesions, amyloid plaques and NFT. The selective presence and accumulation of an abnormal protein is also the distinctive feature of the prion diseases or spongiform encephalopathies.6 In these diseases, the prion protein (PrP), a normal membrane protein of undetermined function, is thought to undergo a conformational change, become partially insoluble, and form aggregates of various sizes in brain including prion amyloid plaques. In several prion diseases, prion plaques are present along with NFTs, which are indistinguishable from those present in AD.9 A major limitation in the study of these abnormal proteins and their relationships is their selective presence in human brain tissue, which is difficult to biopsy and maintain in culture. In a series of studies, Valerie Askanas, King Engel, and co-workers1 -13 have shown that PHF made largely of phosphorylated T and containing ubiquitin epitopes as the PHF of AD, amyloid deposits made of AP3 as the amyloid deposits of AD, fPP, Apo E, and PrP are all present concurrently in muscle fibers of patients with sporadic and hereditary forms of muscle disease called inclusion body myositis and myopathy. In a previous study, these authors showed that f3PP mRNA is increased in the affected muscle fibers of these two conditions.14 In this issue, they report the increase and redistribution of PrP mRNA in the affected muscle fibers. 14 These findings are important on at least four accounts. First, all the abnormal proteins characteristic of AD, ie, abnormal T, AP3, fPP, ubiquitin, and Apo E, are present together and in abnormal amounts in a tissue other than central nervous tissue, and in a disease other than AD and prion diseases. Second, for the first time AP3 amyloid is seen in an intracellular compartment. Third, PrP is also present, along with the abnormal proteins of AD, in the inclusion bodies of these muscle disorders. Fourth, ,BPP and PrP are