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  • Review Article
  • Published:

Therapeutic strategies for Alzheimer's disease

Nature Reviews Drug Discovery volume 1, pages 859–866 (2002)Cite this article

Key Points

  • Cerebral deposition of the amyloid-β peptide (Aβ) in the form of plaques is a defining feature of Alzheimer's disease (AD). The production and aggregation of Aβ does not seem to be simply an epiphenomenon, but is directly implicated in the aetiology of AD. Therefore, decreasing Aβ formation, aggregation and downstream toxic events are all reasonable therapeutic goals.

  • Aβ is produced from the amyloid-β precursor protein (APP) through the action of two proteases, β- and γ-secretase. Both of these proteases are considered important therapeutic targets. The gene that encodes β-secretase can be knocked out without any apparent effect, whereas γ-secretase is crucial for the normal development of the organism. Nevertheless, γ-secretase inhibitors have been reported to lower amyloid levels and reduce brain amyloid deposition in transgenic mice without signs of overt toxicity.

  • The toxic form of Aβ might be soluble oligomers. Therefore, agents that prevent Aβ nucleation could be more effective than those that merely block Aβ deposition. Peptide analogues have been identified that block Aβ nucleation in vitro, one of which prevents amyloid deposition and seems to reduce pathology in transgenic mice.

  • Anti-Aβ immunization, either active or passive, also prevents Aβ plaque formation and the associated pathology in transgenic mice. The first clinical trial for active immunization was cut short because of unacceptable central nervous system (CNS) inflammatory reactions in a small fraction of the subjects. However, modification of this protocol might circumvent this problem.

  • Epidemiological studies indicate that cholesterol-lowering drugs might prevent AD. These agents apparently reduce Aβ production by altering the ability of the secretases to cleave APP. Such findings offer great hope, as these drugs are known to be safe over long periods of time.

  • Other potential strategies for lowering Aβ levels include reducing APP expression at the promoter level and increasing Aβ clearance through the upregulation of Aβ-degrading proteases. Other efforts include developing agents that affect mediators that are downstream of Aβ, such as inhibition of TAU phosphorylation and treatment with antioxidants or anti-inflammatory agents.

Abstract

Alzheimer's disease is a progressive and ultimately fatal neurological disorder for which there is no effective treatment at present. The disease is characterized pathologically by cerebral plaques that contain the amyloid-β peptide and thread-like neuronal structures composed of the microtubule-associated protein TAU. Both amyloid-β and TAU are thought to be crucial to pathogenesis, but compelling evidence supports amyloid-β as the 'prime mover'. The main efforts for developing therapeutics are therefore focused on preventing amyloid-β production, aggregation or downstream neurotoxic events. The progress of these and other approaches raises the hope that effective agents for the prevention and treatment of Alzheimer's disease will be available in the near future.

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Figure 1: APP processing.
Figure 2: β-Secretase inhibitors.
Figure 3: Components of the γ-secretase complex.
Figure 4: γ-Secretase inhibitors.
Figure 5: Inhibitors of Aβ aggregation.

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Acknowledgements

M. S. W. is supported by grants from the National Institutes of Health and the Alzheimer's Association.

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  1. Center for Neurologic Diseases, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, HIM 754, Boston, 02115, Massachusetts, USA

    Michael S. Wolfe

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  1. Michael S. Wolfe
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DATABASES

LocusLink

ACAT

ACHE

APH1

APOE

APP

CDK5

GSK-3β

IDE

M1 receptor

M3 receptor

NCSTN

Notch

PKC

PS1

PS2

renin

SAP

α-secretase

β-secretase

ST6Gal

TAU

ZnT3

OMIM

Alzheimer's disease

FURTHER INFORMATION

Alzheimer's Research Forum

ELS

ELS

Alzheimer disease

amyloidosis

Presenilin Mutations Directory

Glossary

HYPERPHOSPHORYLATION

The addition of more phosphate groups to a protein than is typically observed under normal physiological conditions.

AGGREGATION

The association between large biomolecules that leads to clumping and precipitation.

MISSENSE MUTATION

An alteration in the nucleotide sequence of a gene that changes a single amino-acid residue for another in the encoded protein.

TRANSITION-STATE MIMIC

A small, organic molecule that resembles an intermediate of enzyme catalysis, endowing the compound with inhibitory effects on the enzyme.

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

(NSAIDs). Drugs that prevent or reduce inflammation, but which work by different mechanisms from steroids, such as hydrocortisone.

PHORBOL ESTERS

Natural products that have a distinct, complex carbon skeleton, many of which activate protein kinase C.

COGNITIVE DYSFUNCTION

An impaired ability to remember and learn.

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Wolfe, M. Therapeutic strategies for Alzheimer's disease. Nat Rev Drug Discov 1, 859–866 (2002). https://doi.org/10.1038/nrd938

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