Presentation made by Dr. Dennis Selkoe at the Alzheimer Research Forum Live Webinar of March 20, 2013 - http://www.alzforum.org/res/for/journal/detail.asp?liveID=209

1. Environmental novelty potently prevents impairment of
hippocampal synaptic plasticity by Aβ oligomers
via a β2-adrenergic signaling pathway
Shaomin Li*, Ming Jin*, Dainan Yang,
Ting Yang, Thomas Koeglsperger, Hongjun Fu
and Dennis Selkoe
Center for Neurologic Diseases
Brigham and Women’s Hospital
Harvard Medical School
Neuron - March 6, 2013

2. Expose young mice for 4 weeks (2-6 wk old) to a complex environment of
novel objects they can explore from 9:00 – 5:00. Change the “toys” each day.

3. Golgi staining of hippocampus: dendritic spine area, length
and volume -- but not density – are increased by exposure to EE
Standard housing Enriched environment

4. EE exposure enhances hippocampal LTP

5. EE training prevents LTP inhibition by synthetic Aß S26C dimers,
and importantly, by Aß dimers isolated directly from AD cortex

6. Exposure to EE enhances levels of ß2-AR but not
ß1-AR, DR1, DR2 and other monoamine receptors

7. EE rescue of Aβ-impaired LTP is β-adrenergic dependent

8. Soluble Aß oligomers induce a time-dependent decrease in ß2-AR levels
in hippocampal membranes -- selectively among monoamine receptors
Membrane
b2AR
b1AR
DR1
DR2
TR

9. Prolonged oral administration of a b-adrenergic
antagonist prevents EE from rescuing the Aß inhibition of LTP

10. Prolonged oral administration of the b-adrenergic agonist
isoproternol to SH mice mimics the benefit of EE on LTP

11. Two months of EE in mid-adulthood produces
similar benefit as one month of EE in juvenile mice

12. Novelty vs. exercise in enhancing hippocampal LTP

13. Prolonged exposure to novelty contributes more to prevention
of Aβ-impaired LTP than does prolonged exercise alone

14. Use It or Lose It?
Exposing healthy, wild-type mice to a novel environment produces
several benefits for hippocampal structure and function
These benefits make the EE mice substantially resistant to the acute
synaptic toxicity of soluble Ab oligomers isolated from AD cortex
Among numerous signaling cascades augmented by EE, a b 2-adrenergic
pathway shows more enhancement than other monoamine receptors
Accordingly, we can mimic the EE resistance to Aß oligomers by
prolonged feeding of a b-adrenergic agonist (isoproterenol) to SH mice
Prolonged exposure to a novel environment promotes resistance
to Ab oligomers more effectively than does prolonged exercise
The benefits of EE exposure can be observed not just in
juvenile mice but also in middle-aged mice if done longer