Aβ1-42 alters metabolism and stress response through age-related anorexia
Jorge Iván Castillo-Quan1,2,3,5, Kerri J. Kinghorn1,2,, Dobril Ivanov4, Helena Cochemé1, John Hardy2 and Linda Partridge1,3
1. Institute of Healthy Ageing and Research Department of Genetics, Evolution and Environment, Darwin Building, University College London, Gower Street, London WC1E 6BT, U.K.
2. Department of Molecular Neuroscience. Institute of Neurology, University College London, Queen Square, London WC1N 3BG, U.K.
3. Max Planck Institute for Biology of Ageing, Gleueler Straße 50a, 50931 Köln, Germany.
4. EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hixton, Cambridge, U.K.
4. E-mail: ji.castillo-quan.09@ucl.ac.uk
GRAPHICAL SUMMARY
INTRODUCTORY REMARKS
•  Alzheimer’s disease (AD) is the most prevalent form of neurodegeneration and
poses an important threat to public health.
•  Aβ1-42 oligomers and aggregates are considered the main pathological drivers of
the disease.
•  Several studies have shown that when the Aβ1-42 peptide is expressed in the
neuronal tissue of the fruit fly Drosophila melanogaster, they die earlier than
controls and show abnormalities in locomotor activity and synaptic dysfunction.
Although these phenotypes are useful for genetic and pharmacological screens,
we attempted to characterise earlier phenotypic events.
•  Oxidative stress is amongst the earliest signs of altered cell physiology in AD,
therefore we evaluated the survival response of flies expressing Aβ1-42 to several
pro-oxidants and observed that they showed an age-dependent protection against
paraquat and H2O2 when delivered orally. We decided to investigate the relevance
of this observation.
Aβ1-42
  Neuropeptide F
  Takeout
 hugin
Orexigenic
Anorexigenic
 Feeding Behaviour
NRF-2/cnc
 Fecundity
Sensitivity to Oxidative stress
and Xenobiotics
“Involuntary”
Dietary Restriction/Starvation
 Insulin/IGF-1/mTOR
 Resistance to Starvation
 Triglycerides
Early Death
A LATE ONSET DROSOPHILA MODEL OF ALZHEIMER’S DISEASE
Lifespan reduction
Reduced locomotor ability
Sensitivity to the pro-oxidant paraquat
Resistance to starvation
MECHANISM?
MECHANISM?
(under construction)
(under construction)
Control vs. Aβ1-42
Control vs. hsp70-CncC
(Misra JR, et al. Gen Dev 2011)
Upregulated
Earliest sign of neurodegeneration
Sensitivity to the xenobiotic chloroquine
Downregulated
343
13
159
Downregulated
p = 0.000595
Downregulated
176
23
153
Aβ1-42 represses genes involved in
protection against oxidative/
xenobiotic stress
Aβ1-42 reduces feeding behaviour
p = 9.53e-16
Transcriptional Response
CONCLUDING REMARKS AND RELEVANCE
•  Expression of Aβ1-42 peptide in the neuronal tissue of Drosophila alter the expression of
neuropeptides from the hypothalamic-like circuitry. This translates in reduced feeding behaviour (the
earliest sign of neurodegeneration recorded) and altered metabolism.
•  Poor oral uptake explains why flies exposed to pro-oxidants in their food are age-dependent
resistant, but not when the drugs are injected. A mechanism behind the sensitivity to oxidative/
xenobiotic stress is the repression of genes involved in the protection against these form of stress.
•  We are showing here two avenues (impairment of neuronal physiology/organismal metabolism and
stress-response) for pharmacological interventions. We have also shown that neurons regulating
energy and metabolism are particularly sensitive to Aβ1-42.
Aβ1-42 impairs the hypothalamic-like
circuitry altering metabolism
This work has been
funded by: