The most common amyloidosis is Alzheimer's disease (AD), where A beta is the major component of the amyloid. It has been our working hypothesis since 1985 that central to the pathogenesis of AD are the inherent fibrillogenesis of A beta and the factors which influence fibril formation. We put forward that in AD and Down's syndrome (DS) the progression of the neuropathological lesions goes first through the stage of preamyloid, which in non- fibrillar. These lesions undergo a gradual compaction and fibrillization, producing senile plaques that are associated with neuronal dysfunction and death. Neurofibrillary tangle (NFT) formation appears to be a later change. Our extensive experience with the systemic amyloidoses and work on the Dutch variant of familial AD has led us to the conclusion that a vascular source of A beta contributes significantly to both congophilic angiopathy and senile plaques. As we predicted, it has been recently found that peptides with the same amino acid sequence as A beta exist as a normal soluble protein (sA beta) in biological fluids. This links AD more closely to some of the systemic amyloidoses, where the amyloid precursor is found in the circulation normally. Hence a key question in AD research currently is what factors alter s A beta in the disease state, promoting aggregation, amyloid formation and cerebral toxicity. Numerous mutation have been found in the A beta precursor (beta PP) gene, associated with early onset familial AD. However, A beta deposition typically occurs in the absence of beta PP mutations. Therefore other factors are more important in the majority of AD patients. Thus, we intend to identify by biochemical, immunohistochemical and ultrastructural methods the factors which lead to sA beta deposition and the events which are associated with the progression of preamyloid lesions into neuritic plaques. Recently our biochemical and immunohistochemical studies have shown the importance of two apolipoproteins in amyloidosis: apolipoproteins (apo) E and J. We have proposed, in 1991, that apoE is an A beta chaperone protein, acting to promote and/or stabilize a beta-pleated sheet structure. This hypothesis is supported by the finding that a specific isotype of apoE, E4, is associated with late onset familial and sporadic AD. ApoJ, on the other hand, we have identified as a major carrier of sA beta. ln addition our in vitro studies with A beta peptides have identified aggregation inhibitors or """"""""desaggins"""""""" in normal biological fluids. We hypothesize that a balance exists between factors which promote fibril formation, such as ApoE and desaggrins. These interactions may be critical to determining why sA beta is initially deposited as preamyloid and why preamyloid progresses on to neuritic plaque formation. We proposed to study the following: I) Biochemical and immunohistochemical studies of preamyloid and amyloid in asymptomatic elders, Down's syndrome, AD patients and in an aged dog model of AD. 2) Identification of the conformational alterations and/or posttranslational modifications of sA beta in normal elderly and individuals, including studies on sA beta levels and identification of its chaperone proteins in the normal and disease state. 3) The interactions between A beta and pathological chaperrones, in particular apolipoprotein E, which are critical to amyloid formation and fibrillogenesis. The investigators will provide etiopathogenic mechanisms associated with amyloid deposition the AD brain, amyloid angiopathy and normal aging. The study may also provide the possibility of a diagnostic test and new therapeutic approaches.
| Ghiso, J; Rostagno, A; Tomidokoro, Y et al. (2006) Genetic alterations of the BRI2 gene: familial British and Danish dementias. Brain Pathol 16:71-9 |
| Lashley, T; Holton, J L; Verbeek, M M et al. (2006) Molecular chaperons, amyloid and preamyloid lesions in the BRI2 gene-related dementias: a morphological study. Neuropathol Appl Neurobiol 32:492-504 |
| Fotinopoulou, Angeliki; Tsachaki, Maria; Vlavaki, Maria et al. (2005) BRI2 interacts with amyloid precursor protein (APP) and regulates amyloid beta (Abeta) production. J Biol Chem 280:30768-72 |
| Matsuda, Shuji; Giliberto, Luca; Matsuda, Yukiko et al. (2005) The familial dementia BRI2 gene binds the Alzheimer gene amyloid-beta precursor protein and inhibits amyloid-beta production. J Biol Chem 280:28912-6 |
| Quist, Arjan; Doudevski, Ivo; Lin, Hai et al. (2005) Amyloid ion channels: a common structural link for protein-misfolding disease. Proc Natl Acad Sci U S A 102:10427-32 |
| Rostagno, A; Tomidokoro, Y; Lashley, T et al. (2005) Chromosome 13 dementias. Cell Mol Life Sci 62:1814-25 |
| Calero, Miguel; Rostagno, Agueda; Frangione, Blas et al. (2005) Clusterin and Alzheimer's disease. Subcell Biochem 38:273-98 |
| Morelli, Laura; Llovera, Ramiro E; Alonso, Leonardo G et al. (2005) Insulin-degrading enzyme degrades amyloid peptides associated with British and Danish familial dementia. Biochem Biophys Res Commun 332:808-16 |
| Tomidokoro, Yasushi; Lashley, Tammaryn; Rostagno, Agueda et al. (2005) Familial Danish dementia: co-existence of Danish and Alzheimer amyloid subunits (ADan AND A{beta}) in the absence of compact plaques. J Biol Chem 280:36883-94 |
| Ghiso, Jorge; Shayo, Marcos; Calero, Miguel et al. (2004) Systemic catabolism of Alzheimer's Abeta40 and Abeta42. J Biol Chem 279:45897-908 |
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