Impact of Locus Coeruleus Degenerationin Alzheimer´s Disease

Michael T. HenekaClincal Neuroscience Unit, University of Bonn andGerman center for Neurodegenerative Disease

Alzforum, 20.03.2013

Anatomy and function

LC pathology in AD

CON AD

Aggravating spatial memory dysfunction

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Heneka et al. J.Neurosci. , 2006

dsp4 – induced LC degeneration in APP23 mice

• Mice were habituated to theapparatus for 4 days.

• A male mouse was presentedfor 5 minutes at the test day.

• One hour later the sameanimal was represented.

Social memory dysfunction

Ear2 ko (LC loss) vs DBH ko (NA loss)

Hammerschmidt et al. Biol.Psychiatry, 2012

Effects on synaptic plasticity

L-threo-DOPS restores NE in the cortex andhippocampus

Thomas et al. J.Neurochem. 1998Heneka et al. PNAS 2010

Behavioural improvement by L-threo DOPS

Modulation of the synaptosome

Partial protection of β-CaMKIIpThr286

Summary

Locus ceruleus degeneration represents an early event in AD

Loss of LC and NE in LC projection areas may cause early memorydysfunction

IF EE mediated effects are mediated by LC derived NA – can they beexpected in AD patients?

Could EE/cognitive strategies slow disease progression more effectivelywhen patients receive NA substitution by L-threo DOPS?

What´s the cause of LC degeneration and does EE delay/prevent it?