precursor protein (APP) by β- and γ

precursor protein (APP) by β- and γ- secretase,
in AD. Similarly, mutations in the tau gene lead to
familiar tauopathies.
Autosomal dominant mutations in APP are cor-
related with rare cases of early-onset AD. Deter-
mining the in vivo functions of APP is difficult be-
cause mammals have an APP gene family contain-
ing two APP-related genes. C. elegans has a single
APP-related gene, apl-1 mapped on the X chromo-
some. The apl-1 gene is expressed in multiple cell
types and is necessary for many developmental
processes, including proper molting and morpho-
genesis. Loss of apl-1 causes larval lethality, which
can be rescued by neuronal expression of the ex-
tracellular domain of APL-1. Similarly, the overex-
pression of APL-1 causes defects in movement,
brood size and larval viability of transgenic nema-
todes. The apl-1 overexpression-induced lethality
is partially rescued by the reduced activity of sel-
12,a C. elegans homologue of the human γ-secre-
tase gene component presenilin 1, suggesting that
SEL-12, like mammalian PS1, regulates the activi-
ty of APL-1 either directly or indirectly [13].
C. elegans AD models were developed that ex-
press Aβ variants under the control of male-specif-
ic, body wall muscle-specific and neuronal-specif-
ic promoters. Only transgenic lines carrying the
unc-54/Aβ1–42
minigene accumulate intracellular
Aβ, and show a progressive paralysis beginning in
young adulthood. Co-immunoprecipitation studies
coupled with mass spectrometry reveal that chap-
erone-related proteins (two human HSP70, three
HSP-16 homologous to αB-crystallin and a putative
negative regulator of HSP70 function) interact with
Aβ in vivo.This interaction is considered as part of
a cellular protective response since the overex-
pression of either HSP-16.2 or a human HSP70
partially suppresses the Aβ-induced paralysis in
worms [14]. Heat shock treatment reduces Aβ
oligomeric protein and delays paralysis in trans-
genic Aβ worms, probably through the activation of
heat shock proteins regulated by the heat shock
transcription factor 1 (HSF-1) [15].HSF-1 has been
coupled to normal ageing and age-related diseases
[16]. Previous studies showed that constituents of
Ginkgo biloba leaf extract (EGb 761 and ginkgo-
lides) delay β-amyloid-induced paralysis in trans-
genic C. elegans [17].This effect was not additive to
protective heat shock, suggesting a shared mecha-
nism of action by the two treatments [15].Microar-
ray analysis in a transgenic worm strain that accu-
rately expresses a temperature-inducible Aβ42 in
body wall muscle, reveals that the gene encoding
the arsenite-inducible protein (aip-1) is up-regu-
lated as part of a cellular protective response.
Worms overexpressing AIP-1 show decreased ac-© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1263
cumulation of Aβ42
peptide and attenuated paraly-
sis.The AIP-1 human homologue,AIRAPL, but not
AIRAP when expressed under the control of myo-
3 promoter also confers protection against Aβ toxi-
city [18]. Both AIP-1 and AIRAPL contain a pre-
dicted farnesylation site known to be critical for the
AIP-1-mediated longevity in C. elegans [19].AIP-1
and AIRAPL enhance at least partially general pro-
tein turnover by acting as positive regulators of
proteosomal function, and thus protect against Aβ-
induced toxicity [18].The effects of tetracycline and
its analogues doxycycline and minocycline on Aβ42-
induced toxicity were assayed [20] using the worms
expressing a temperature-inducible Aβ1–42 trans-
gene [21]. Tetracyclines successfully protected
transgenic worms from the Aβ insult by reducing
the concentration of oligomers considered to be re-
sponsible for the toxic phenotype. These effects
were specific, dose-dependent and not linked to
any antibiotic activity. Furthermore, tetracyclines
protect Aβ-expressing nematodes from oxidative
stress by reducing the superoxide production, sug-
gesting a potential use of these drugs in targeting
Aβ aggregates