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Alzheimer's Disease (AD) is defined histopathologically by extracellular [beta]-amyloid (A[beta]) fibrils plus intraneuronal tau filaments. Studies of transgenic mice and cultured cells indicate that AD is caused by a pathological cascade in which A[beta] lies upstream of tau, but the steps that connect A[beta] to tau have remained undefined. We demonstrate that tau confers acute hypersensitivity of microtubules to prefibrillar, extracellular A[beta] in nonneuronal cells that express transfected tau and in cultured neurons that express endogenous tau. Prefibrillar A[beta]42 was active at submicromolar concentrations, several-fold below those required for equivalent effects of prefibrillar A[beta]40, and microtubules were insensitive to fibrillar A[beta]. The active region of tau was localized to an N-terminal domain that does not bind microtubules and is not part of the region of tau that assembles into filaments. These results suggest that a seminal cell biological event in AD pathogenesis is acute, tau-dependent loss of microtubule integrity caused by exposure of neurons to readily diffusible A[beta].

The transmembrane protein amyloid-[beta] precursor protein (APP) and the vesicle-associated protein c-Jun N[H.sub.2]-terminal kinase-interacting protein-1 (JIP-1) are transported into axons by kinesin-1. Both proteins may bind to kinesin-1 directly and can be transported separately. Because JIP-1 and APP can interact, kinesin-1 may recruit them as a complex, enabling their cotransport. In this study, we tested whether APP and JIP-1 are transported together or separately on different vesicles. We found that, within the cellular context, JIP-1 preferentially interacts with [Thr.sup.668]-phosphorylated APP (pAPP), compared with nonphosphorylated APP. In neurons, JIP-1 colocalizes with vesicles containing pAPP and is excluded from those containing nonphosphorylated APP. The accumulation of JIP-1 and pAPP in neurites requires kinesin-1, and the expression of a phosphomimetic APP mutant increases JIP-1 transport. Down-regulation of JIP-1 by small interfering RNA specifically impairs transport of pAPP, with no effect on the trafficking of nonphosphorylated APP. These results indicate that the phosphorylation of APP regulates the formation of a pAPP-JIP-1 complex that accumulates in neurites independent of nonphosphorylated APP.

Introducing mutations within the amyloid precursor protein (APP) that affect [beta]- and [gamma]-secretase cleavages results in amyloid plaque formation in vivo. However, the relationship between [beta]-amyloid deposition and the subcellular site of A[beta] production is unknown. To determine the effect of increasing [beta]-secretase (BACE) activity on A[beta] deposition, we generated transgenic mice overexpressing human BACE. Although modest overexpression enhanced amyloid deposition, high BACE overexpression inhibited amyloid formation despite increased [beta]-cleavage of APP. However, high BACE expression shifted the subcellular location of APP cleavage to the neuronal perikarya early in the secretory pathway. These results suggest that the production, clearance, and aggregation of A[beta] peptides are highly dependent on the specific neuronal subcellular domain wherein A[beta] is generated and highlight the importance of perikaryal versus axonal APP proteolysis in the development of A[beta] amyloid pathology in Alzheimer's disease.

In addition to its documented role in the proteolytic processing of Notch-1 and the [Beta]-amyloid precursor protein, presenilin 1 (PS1) associates with [Beta]-catenin. In this study, we show that this interaction plays a critical role in regulating [Beta]-catenin/T Cell Factor/Lymphoid Enhancer Factor-1 (LEF) signaling. PS1 deficiency results in accumulation of cytosolic [Beta]-catenin, leading to a [Beta]-catenin/LEF-dependent increase in cyclin D1 transcription and accelerated entry into the S phase of the cell cycle. Conversely, PS1 specifically represses LEF-dependent transcription in a dose-dependent manner. The hyperproliferative response can be reversed by reintroducing PS1 expression or overexpressing axin, but not a PS1 mutant that does not bind [Beta]-catenin (PS1[Delta]cat) or by two different familial Alzheimer's disease mutants. In contrast, PS1[Delta]cat restores Notch-1 proteolytic cleavage and A[Beta] generation in PS1-deficient cells, indicating that PS1 function in modulating [Beta]-catenin levels can be separated from its roles in facilitating [Gamma]-secretase cleavage of [Beta]-amyloid precursor protein and in Notch-1 signaling. Finally, we show an altered response to Wnt signaling and impaired ubiquitination of [Beta]-catenin in the absence of PS1, a phenotype that may account for the increased stability in PS1-deficient cells. Thus, PS1 adds to the molecules that are known to regulate the rapid turnover of [Beta]-catenin. Key words: presenilin * [Beta]-catenin * Notch-1 * [Beta]-amyloid precursor protein * cyclin D1

Amyloid fibrils, such as those found in Alzheimer's and the gelsolin amyloid diseases, result from the misassembly of peptides produced by either normal or aberrant intracellular proteolytic processing. A paper in this issue by Marks and colleagues (Berson et al., 2003) demonstrates that intra-melanosome fibrils are formed through normal biological proteolytic processing of an integral membrane protein. The resulting peptide fragment assembles into fibrils promoting the formation of melanin pigment granules. These results, along with the observation that amyloid fibril formation by bacteria is highly orchestrated, suggest that fibril formation is an evolutionary conserved biological pathway used to generate natural product nanostructures.