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SAGE KE Bulletin Board

Alzheimer’s disease: Relevance of changes in the amino acid sequence of amyloid ß-protein (Aß)

21 November 2005

Dietmar R. Thal

Highlights of the 35th Annual Meeting of the Society for Neuroscience 2005 in Washington DC:

Alzheimer’s disease: Relevance of changes in the amino acid sequence of amyloid ß-protein (Aß) on the formation of oligomeric and fibrillar Aß and its toxicity

Variations in the amino acid sequence of Aß have been described to modulate the toxicity of Aß. Aß42 mutants on positions 22 and 23 (E22Q- and E23K-Aß42) were 50-200 times more neurotoxic than the wildtype peptide (3). As an explanation for the increase in neurotoxicity an increased ß-sheet formation was suggested (3). An increased tendency for developing salt bridges between Lys22 and Asp23 appeared to be responsible for this effect (5). Murakami et al. (6) discussed on the basis of their experiments that Aß fibrils with mutations on positions 22 and 23 have a higher affinity to contain radical species within the fibrils explaining the higher neurotoxicity of these Aß fibrils compared to those of wildtype Aß. Although mutations of the amino acids 22 and 23 lead to an increased tendency to build fibrils patients carrying these mutations exhibit familial cerebral amyloid angiopathy of the Dutch-type (E22Q) and the Iowa-type (E23N) and plaque deposition is limited. Hoos and van Nostrand (2) isolated a 20 kD protein from brain homogenates that was able to inhibit fibril formation of Dutch and Iowa type Aß in the brain parenchyma while wildtype Aß was able to fibrillize. Thus, Dutch-type and Iowa-type Aß starts building fibrils in the vessel wall while Aß- deposition in the brain parenchyma is inhibited. The presence of calcium (Ca++) is a prerequisite for the aggregation of protofibrils to amyloid fibrils. Thereby, protofibrils appeared to be less neurotoxic in comparison to amyloid fibrils (4). In addition, studies of transgenic mice exhibiting the Arctic mutation in the APP gene (ARC6 mice) showed higher Aß-plaque levels in the brain as mice exhibiting human wildtype APP but less severe deficits in learning and memory tasks as well as less neuronal depletions of calbindin and FOS (1). On the other hand, transgenic mice carrying both the Arctic as well as the Swedish mutation showed higher levels of soluble Aß aggregates than mice carrying only the Swedish mutation (7). A possible explanation for this finding is the increased occurrence of intraneuronal Aß in ARCSWE-mice.

In summary, these results presented on the 35th Annual meeting of the Society for Neuroscience provide evidence that mutations within the Aß amino acid sequence modulate the toxicity of the Aß peptide by interacting with its tendency to create fibrils and oligomeres. This property of Aß is further modulated by the milieu of the extracellular space (protective proteins, Ca++ levels).

References

1. I.H.Cheng, K.Scearce-Levie, J.J.Palop, J.Puolivali, L.Mucke. Increased plaque formation may delay functional neuronal deficits in Arctic - mutant human amyloid precursor protein transgenic mice Program No. 324.3. 2005 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience

2. M.D.Hoos, W.E.Van Nostrand. Endogenous brain inhibitor of familial cerebral amyloid angiopathy mutant amyloid - beta protein fibril formation Program No. 359.13. 2005 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience

3. K.Irie, K.Murakami, Y.Masuda, A.Morimoto, H.Ohigashi, M.Nagao, T.Shimizu, T.Shirasawa. New aggregation model of 42 - mer amyloid - beta by the systematic proline replacement Program No. 134.12. 2005 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience

4. A.M.Isaacs, D.B.Senn, M.Yuan, J.P.Shine, B.A.Yankner. Marked augmentation of amyloid beta - protein protofibril to fibril conversion by physiological concentrations of calcium Program No. 359.1. 2005 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience

5. Y.Masuda, K.Irie, K.Murakami, H.Ohigashi, R.Ohashi, K.Takegoshi, T.Shimizu, T.Shirasawa. Elucidation of the "malignant" conformation of beta - amyloid with Italian mutation ( E22K - A�242 ) using solid - state NMR: implications for the pathogenesis of cerebral amyloid angiopathy and Alzheimer's disease Program No. 134.13. 2005 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience

6. K.Murakami, K.Irie, H.Ohigashi, H.Hara, M.Nagao, T.Shimizu, T.Shirasawa. Alzheimer's 42 - mer Abeta peptide - specific mechanism of neurotoxicity through radical formation Program No. 134.14. 2005 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience

7. L.N.G.Nilsson, A.Lord, O.Philipsson, H.Englund, C.Stenh, H.Kalimo, C.Eckman, L.Lannfelt. Alzheimer's disease transgenic mice with both Arctic and Swedish APP mutations: a novel animal model for enhanced mechanistic understanding and therapeutic targeting of Abeta oligomerization Program No. 359.4. 2005 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience


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