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New drug target in Alzheimer’s disease

Ref-Nr: TA-B74174


Kurzfassung

  • 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/applicati- on 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


Hintergrund

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.


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Lösung

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

Vorteile

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


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