Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: a potential model for Alzheimer's disease - PubMed (original) (raw)

Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: a potential model for Alzheimer's disease

Koichi Iijima et al. Proc Natl Acad Sci U S A. 2004.

Abstract

Accumulation of amyloid-beta (Abeta) 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 Abeta40 or Abeta42 peptide in the Drosophila brain can induce pathological phenotypes resembling AD. The expression of Abeta42 led to the formation of diffused amyloid deposits, age-dependent learning defects, and extensive neurodegeneration. In contrast, expression of Abeta40 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 Abeta42 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 Abeta toxicity and the discovery of novel therapeutic targets for AD.

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Figures

Fig. 1.

Expression and accumulation profiling of Aβ in transgenic fly heads. (A) Expression levels of Aβ peptides in SDS-soluble (Left) and FA fraction (Right) at 3 days old. (B) Confirmation of the intactness of Aβ40 or Aβ42. 6E10 recognizes the common part of Aβ40 and Aβ42, whereas the 40 or 42 antibody is specific to each C terminus. (C) Age-dependent accumulation of Aβ peptides in SDS-soluble (Upper) and FA fraction (Lower). Arrowheads, monomeric Aβ; asterisks, putative oligomeric forms. (D) Mass spectrometric analysis of Aβ peptide from Aβ40 (Upper) or Aβ42 transgenic fly heads (Lower).

Fig. 2.

Detection of Aβ deposits in fly brain. (A-H) Whole-mount Aβ immunostaining (green) and nuclear staining (red) in the neuropil region (A-D) and Kenyon cell layer (E-H). Arrowheads, deposited Aβ42 (A and B); asterisks, the peduncle structure, an axon bundle of Kenyon cells. (I-N) ThioflavinS staining in the Kenyon cell (I-K) and neuropil regions (L-N). ThioflavinS-positive deposits were detected in Aβ42 flies (I, arrows) but not in Aβ40 or control (J and K, arrowheads). The fiber structures seen in I-K are tracheas. Pd, peduncle; Kn, Kenyon cell layer; Ca, calyx; the dendritic structure of Kenyon cells. [Bar (D, H, and N) = 50 μm.]

Fig. 3.

Progressive loss of learning ability in Aβ flies assayed by a Pavlovian olfactory associative learning paradigm. (A-C) Learning abilities at 2-3 (A), 6-7 (B), and 14-15 days old (C) are presented in mean ± SEM. The numbers of experiments are indicated on top of the bars. Asterisks show statistical difference from controls [(α<0.05, Tukey-Kramer honestly significant difference (HSD)]. (D) No statistical difference in olfactory acuity and shock reactivity between experimental genotype and appropriate control genotypes at 14-15 days old (n = 8; except n = 6 for octanol olfactory acuity for elav/_Y;UASA_β42/+ and shock reactivity for _UAS-A_β40/+) at the level of α = 0.05 (Tukey-Kramer HSD).

Fig. 4.

Progressive climbing disability and shortened life span in Aβ42 flies. (A, C, and E) Climbing ability in Aβ42 flies (A and C, asterisks, P < 0.001, Student's t test) and Aβ40 flies (E). The SDs of 10 trials are within the symbols. (B, D, and F) Survival rate of Aβ42 flies (B and D) and Aβ40 flies (F).

Fig. 5.

Late-onset progressive neurodegeneration in Aβ42 brains. (A-H) Progressive neuronal loss occurred in Aβ42 (A-F, arrowheads) but not in Aβ40 or control brains (G and H). (A-D, G, and H) The Kenyon cell region. (E) Medial brain. (F) Lateral brain. Green, neuropil structure; red, nuclei. Arrows in D indicate the aggregates, presumably amyloid deposits. Kn, Kenyon cell layer; Ca, calyx; PB, protocerebral bridge; OL, optic lobe. [Bars (C and H) = 50 μm.] (I) Neuronal loss induced by different Gal4 line, OK107. (Bar = 50 μm.) (J) Ultrastructural analysis of degenerating neurons with digested cytoplasm (electron-lucent) and swollen mitochondria (arrows). N, nucleus. (Bar = 1 μm.)

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Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: a potential model for Alzheimer's disease - PubMed (original) (raw)