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Sep 16, 2017

New drug target in Alzheimer’s disease

Life Sciences, Neurology/CNS

  • Aη-α as a new drug target and / or diagnostic marker for Alzheimer’s disease
  • Inhibition of β-secretase leads to accumulation of Aη-α
  • Antibodies to detect η-secretase pathway peptides are available

Your contact

Dr. Rebecca Kohler

E-Mail:
rkohler@baypat.de
Phone:
+49 (0) 89 5480177 - 33
Reference Number:
B74174

Challenge

Alzheimer’s disease (AD) is characterized by large numbers of senile plaques consisting of ­amyloid beta protein (Aβ). Aβ results from amyloid precursor protein (APP), which is cleaved by β-secretase and γ-secretase. The APP processing pathway is therefore a prominent target of current therapeutic approaches like secretase blocker or inhibitors that prevent ­aggregation of amyloid plaques.

Innovation

Here a new physiological APP processing is described, which generates proteolytic ­fragments capable of inhibiting neuronal activity in the hippocampus. This discovery offers new ­opportunities for therapeutic and diagnostic approaches, and should be considered in ­current therapy strategies.


Highlights

  • CTF-η and Aη peptides are present in dystrophic neurites in brains derived from an AD mouse model (APPPS1-21 mice) as well as in human AD brains
  • CTF-η and Aη-α fragments accumulate after β-secretase BACE1 inhibition and are ­enriched in dystrophic neurites
  • η-secretase activity is highly increased in dystrophic neurites with close vicinity to Aβ-plaques
  • Aη-α impairs hippocampal long term potentiation (LTP)
  • Aη-α strongly suppresses the activity of hippocampal neurons in vivo, an effect not ­observed with Aη-β or the control peptide
  • by using local application of synthetic Aη-α to hippocampal neurons, the inhibitory effect of Aη-α on neurons is readily reversible after washout

Commercial Opportunities

  • Aη-α as a new drug target and / or diagnostic marker for Alzheimer disease
  • Presence of Aη-α fragments in AD brains should be taken into account for development/application
  • of drugs targeting Aβ or inhibiting β-secretase, since these lead to accumulation of Aη-α
  • Antibodies to detect η-secretase pathway peptides are available

Development Status

Contact us for more information

References

  • Reference:

    Willem et al., Nature 526, 443–447

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