Accumulation of amyloid-␤ (A␤) peptides in the brain has been suggested to be the primary event in sequential progression of Alzheimer's disease (AD). Here, we use Drosophila to examine whether expression of either the human A␤40 or A␤42 peptide in the Drosophila brain can induce pathological phenotypes resembling AD. The expression of A␤42 led to the formation of diffused amyloid deposits, age-dependent learning defects, and extensive neurodegeneration. In contrast, expression of A␤40 caused only age-dependent learning defects but did not lead to the formation of amyloid deposits or neurodegeneration. These results strongly suggest that accumulation of A␤42 in the brain is sufficient to cause behavioral deficits and neurodegeneration. Moreover, Drosophila may serve as a model for facilitating the understanding of molecular mechanisms underlying A␤ toxicity and the discovery of novel therapeutic targets for AD. A lzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by progressive decline in memory accompanied by histological changes, including neuronal loss and the formation of neurofibrillary tangles (NFTs) and senile plaques (1). The accumulation of amyloid-␤ (A␤)42 peptide, the major component of senile plaques, has been hypothesized to be the primary event in AD pathogenesis (2, 3). The strongest support for the A␤ hypothesis comes from genetic analyses of familial AD (FAD); most FAD mutations identified in A␤ precursor protein (APP), Presenilin1 (PS1) and Presenilin2 (PS2) genes appear to cause excessive accumulation of A␤42 (4). Secretion of A␤ peptides is a result of sequential cleavage of APP by ␤-secretase, a type I transmembrane glycosylated aspartyl protease, and ␥-secretase, a large protein complex that includes at least four proteins, Presenilins (PS1 or PS2), Nicastrin, Aph-1, and Pen-2 (for review, see ref. 5). The heterogeneity of ␥-secretase cleavage gives rise to a series of A␤ peptides, including the major species A␤40 and a smaller amount of A␤42.To study AD pathogenesis in vivo, a number of AD mouse models have been established and have successfully recapitulated AD-like phenotypes, including abundant amyloid deposits, astroglial activation, synaptic loss and dysfunction, behavioral abnormalities, and neurodegeneration (6-15). In addition to these mouse models, the model systems that allow highthroughput genetic screening will facilitate the discovery of genes involved in AD pathogenesis. Furthermore, one of the intriguing issues that have not been elucidated in these transgenic mice is the pathological roles of each specific A␤ species (i.e., A␤40 and A␤42), because currently available mouse models mainly rely on overexpression of APP.We use a Drosophila model (16) to compare the specific pathological roles of A␤40 and A␤42. In Drosophila, all components involved in the protein complex responsible for ␥-secretase activity are highly conserved (17), whereas ␤-secretase activity is absent or very low (18). An APP-like protein (APPL) is also present in flies, althou...

An anatomical and electrophysiological study of Drosophila mutants has been made to determine the effect of altered electrical activity on the development and maintenance of larval neuromuscular junctions. We examined motor axon terminals of (1) hyperexcitable mutants Shaker (Sh), ether a go-go (eag), Hyperkinetic (Hk), and Duplication of para+ (Dp para+); and (2) mutants with reduced excitability, no action potential (napts) and paralytic (parats 1). Nerve terminals innervating larval body-wall muscles were visualized by using anti-HRP immunocytochemistry, which specifically stains neurons in insect species. In wild-type larvae, motor axon terminals were distributed in a stereotypic fashion. However, in combinations of eag and Sh alleles, the basic pattern of innervation was altered. There was an increase in both the number of higher-order axonal branches over the muscles and the number of varicosities on the neurites. A similar phenomenon was found in the double mutant Hk eag and, to a lesser extent, in Dp para+ and Dp para+ Sh mutants. It is known that at permissive temperature the napts, but not parats 1, mutation decreases excitability of larval motor axons and suppresses the behavioral phenotypes of Sh, eag, and Hk. In the mutant napts (reared at permissive temperature), a slight decrease in the extent of branching was observed. Yet, when combined with eag Sh, napts completely reversed the morphological abnormality in eag Sh mutants. No such reversion was observed in parats 1 eag Sh mutants. The endogenous patterns of electrical activity at the neuromuscular junction were analyzed by extracellular recordings in a semi-intact larval preparation. Recordings from wild-type body-wall muscles revealed rhythmic bursts of spikes. In eag Sh mutants, this rhythmic activity was accompanied by or superimposed on periods of strong tonic activity. This abnormal pattern of activity could be partially suppressed by napts in combination with eag Sh.

Initially acquired memory dissipates rapidly if not consolidated. Such memory decay is thought to result either from the inherently labile nature of newly acquired memories or from interference by subsequently attained information. Here we report that a small G protein Rac-dependent forgetting mechanism contributes to both passive memory decay and interference-induced forgetting in Drosophila. Inhibition of Rac activity leads to slower decay of early memory, extending it from a few hours to more than one day, and to blockade of interference-induced forgetting. Conversely, elevated Rac activity in mushroom body neurons accelerates memory decay. This forgetting mechanism does not affect memory acquisition and is independent of Rutabaga adenylyl cyclase-mediated memory formation mechanisms. Endogenous Rac activation is evoked on different time scales during gradual memory loss in passive decay and during acute memory removal in reversal learning. We suggest that Rac's role in actin cytoskeleton remodeling may contribute to memory erasure.