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Targeting amyloid clearance in Alzheimer's disease as a therapeutic strategy

Natalia N Nalivaeva1,2, Anthony J Turner1

  • 1School of Biomedical Sciences, University of Leeds, Leeds, UK.

British Journal of Pharmacology
|February 3, 2019
PubMed

Insights

Alzheimer's disease (AD) drug development is shifting focus from amyloid-beta (Aβ) production to enhancing its clearance. Targeting amyloid-degrading enzymes (ADEs) and improving physiological clearance mechanisms offers new therapeutic hope.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Biochemistry

Background:

  • Alzheimer's disease (AD) research has long focused on the amyloid-beta (Aβ) cascade, yet successful therapeutics remain elusive.
  • Evidence strongly implicates Aβ in AD pathogenesis, with current strategies targeting its biosynthesis via secretase inhibitors.
  • Aβ levels are regulated by both production and clearance, with clearance failure potentially driving late-onset AD.

Purpose of the Study:

  • To review the mechanisms of Aβ clearance in the brain, focusing on amyloid-degrading enzymes (ADEs).
  • To explore the therapeutic potential of targeting ADEs and other clearance pathways for AD drug development.
  • To discuss modifiable physiological factors influencing Aβ clearance efficiency.

Main Methods:

  • Review of existing literature on Aβ clearance mechanisms, ADEs, and related physiological factors.
  • Analysis of the role of zinc metalloproteases, including neprilysin (NEP), insulin-degrading enzyme, and angiotensin-converting enzymes (ACE).
  • Discussion of therapeutic strategies to up-regulate ADE expression and activity (genetic, epigenetic, pharmacological).

Main Results:

  • Aβ clearance involves proteolysis by ADEs and transport processes; failure in clearance is linked to late-onset AD.
  • Key ADEs are zinc metalloproteases, presenting viable targets for therapeutic intervention.
  • Strategies to enhance ADE activity and improve physiological clearance (e.g., brain perfusion, metabolic health) are promising.

Conclusions:

  • Shifting therapeutic focus to Aβ clearance mechanisms, rather than solely production, offers new avenues for AD treatment.
  • Targeting ADEs and optimizing physiological clearance pathways hold significant potential for future AD drug development.
  • Enhanced understanding of Aβ clearance provides optimism for developing effective Alzheimer's disease therapies.

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