Alzheimer's Disease: Genes, Proteins, and Therapy

Dennis J. Selkoe

doi:10.1152/physrev.2001.81.2.741

journal article Apr 01, 2001

Alzheimer's Disease: Genes, Proteins, and Therapy

Dennis J. Selkoe

Physiological Reviews Vol. 81 No. 2 pp. 741-766 · American Physiological Society

View at Publisher Save 10.1152/physrev.2001.81.2.741

Abstract

Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-secretase, coupled with the recent identification of β-secretase, has provided discrete biochemical targets for drug screening and development. Alternate and novel strategies for inhibiting the early mechanism of the disease are also emerging. The progress reviewed here, coupled with better ability to diagnose the disease early, bode well for the successful development of therapeutic and preventative drugs for this major public health problem.

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References

211

[1]

10.1016/0092-8674(88)90462-x

[2]

10.1006/bbrc.1999.1295

[3]

10.1083/jcb.147.2.277

[4]

10.1126/science.284.5415.770

[5]

10.1038/ng1197-263

[6]

10.1046/j.1365-4624.1997.00012.x

[7]

10.1016/0092-8674(94)90131-7

[8]

10.1046/j.1471-4159.2000.0750583.x

[9]

10.1006/nbdi.1995.0019

[10]

10.1038/1243

[11]

10.1016/s0896-6273(00)80230-5

[12]

Brion J Arch Biol (1985)

[13]

10.1073/pnas.90.5.2092

[14]

10.1074/jbc.273.6.3205

[15]

10.1038/nm0197-67

[16]

10.1038/nm0997-1021

[17]

10.1038/ng0694-180

[18]

10.1126/science.8346443

[19]

10.1016/s0197-4580(98)00042-6

[20]

10.1016/s0896-6273(00)80998-8

[21]

A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain

Bart De Strooper, Wim Annaert, Philippe Cupers et al.

Nature 10.1038/19083

[22]

Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein

Bart De Strooper, Paul Saftig, Katleen Craessaerts et al.

Nature 10.1038/34910

[23]

10.1083/jcb.121.2.295

[24]

10.1097/00005072-199704000-00001

[25]

10.1212/wnl.54.2.438

[26]

10.1038/383710a0

[27]

10.1038/382716a0

[28]

10.1126/science.2111583

[29]

10.1038/35017062

[30]

10.1073/pnas.92.3.763

[31]

10.1038/373523a0

[32]

10.1021/bi00412a006

[33]

10.1002/ana.410390320

[34]

10.1097/00005072-199301000-00004

[35]

10.1016/s1097-2765(00)80219-1

[36]

10.1016/0006-291x(84)91209-9

[37]

10.1016/s0006-291x(84)80190-4

[38]

10.1038/349704a0

[39]

10.1097/00005072-198611000-00004

[40]

10.1016/s0002-9440(10)64700-1

[41]

10.1002/ana.410380219

[42]

10.1101/gad.12.12.1751

[43]

10.1073/pnas.86.19.7611

[44]

10.1073/pnas.83.13.4913

[45]

Haass C J Biol Chem (1993) 10.1016/s0021-9258(18)53650-4

[46]

10.1523/jneurosci.11-12-03783.1991

[47]

Haass C J Biol Chem (1994) 10.1016/s0021-9258(17)32503-6

[48]

10.1083/jcb.128.4.537

[49]

10.1073/pnas.91.4.1564

[50]

10.1038/nm1295-1291

Showing 50 of 211 references

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References

Details

Published: Apr 01, 2001
Vol/Issue: 81(2)
Pages: 741-766

Authors

D

Dennis J. Selkoe

Department of Neurology and Program in Neuroscience, Harvard Medical School, and Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts

Cite This Article

Dennis J. Selkoe (2001). Alzheimer's Disease: Genes, Proteins, and Therapy. Physiological Reviews, 81(2), 741-766. https://doi.org/10.1152/physrev.2001.81.2.741

Alzheimer's Disease: Genes, Proteins, and Therapy

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