Likewise, cellular seeding with ??-syn fibrils induces the formation of cytotoxic neurofibrillary our site tangle-like inclusions [35]. Extracellular seeding of ??-syn fibrils can also promote recruitment of soluble ??-syn into insoluble Lewy body-like inclusion bodies [36]. Transgenic models that combine ??-amyloid and ??-synuclein pathology Mouse models of overlapping A?? and ??-syn pathology lend further support to the theory that A?? and ??-syn interact synergistically to create a more severe disease course. Double-transgenic mice expressing human amyloid precursor protein (APP) and wild-type hSYN develop motor deficits at 6 months compared with 12 months in single-transgenic hSYN mice [19]. These human APP/hSYN mice also develop spatial memory deficits and increased numbers of Lewy body-like inclusions [19].

These double-transgenic mice therefore provide a useful model for examining the potential interactions between A?? and ??-syn. To model all three of the pathologies that co-exist within AD-LBV patients, Clinton and colleagues crossed 3xTg-AD transgenic mice with a mutant ??-synuclein transgenic line [22]. The 3xTg-AD model develops A?? plaque and neurofibrillary tangle pathology via co-expression of mutant APP, mutant presenilin-1, and mutant tau. By adding a mutant ??-syn (A53T) transgene to the mix, this model (hereafter referred to as AD-LBV mice) success-fully recapitulated all three major AD-LBV pathologies [22]. Interestingly, AD-LBV mice exhibit accelerated cognitive dysfunction versus 3xTg-AD or ??-syn lines, suggesting that this complex model mimics an important feature of AD-LBV.

Similar to the single-transgenic ??-syn mouse, the AD-LBV mice develop Lewy body-like Anacetrapib inclusions. However, AD-LBV mice show increased levels of insoluble ??-syn, pS129-syn, and Lewy body pathology at much earlier ages than single-transgenic ??-syn mice. Two other pathological results of interest are that AD-LBV mice develop increased levels of insoluble A??42 tau at younger ages than 3xTg-AD mice. Although this model uses mutant transgenes, the results nevertheless provide important additional evidence that A??, tau, and ??-syn can interact synergistically to accelerate pathogenesis and cognitive decline. While much of the in vivo evidence linking A?? and ??-syn comes from the use of transgenic mice that express mutant genes, the study of these models has yielded invaluable additions to our knowledge of neurodegenerative disease [1,18,37].

Importantly, similar results have been found in models regardless of whether mutant http://www.selleckchem.com/products/brefeldin-a.html [22] or wild-type [19] ??-syn transgenes were utilized. Interestingly, investigations of familial AD presenilin 1, presenilin 2, and APP mutation carriers also reveal increased development of Lewy body pathology [38-40]. Both mouse models and human cases thus suggest that disease-associated APP and presenilin mutations can enhance the pathological accumulation of wild-type ??-syn.