0

The full content of Annals is available to subscribers

Subscribe/Learn More  >
Reviews |

Alzheimer Disease: Mechanistic Understanding Predicts Novel Therapies

Dennis J. Selkoe, MD
[+] Article and Author Information

From Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts.


For definition of terms used, see Glossary.

Acknowledgments: The author thanks his colleagues and collaborators for many helpful discussions.

Grant Support: By the National Institutes of Health, Alzheimer's Association, and the Foundation for Neurologic Diseases. Dr. Selkoe is a founding scientist of Athena Neurosciences, now Elan Corporation.

Potential Financial Conflicts of Interest:Honoraria and Patents received: Elan Corp.

Requests for Single Reprints: Dennis J. Selkoe, MD, Center for Neurologic Diseases, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, HIM 730, Boston, MA 02115.


Ann Intern Med. 2004;140(8):627-638. doi:10.7326/0003-4819-140-8-200404200-00010
Text Size: A A A

In contrast to research for disorders such as Parkinson and Huntington diseases, in which the cloning of novel causative genes led to the development of biochemical hypotheses, Alzheimer disease research has largely developed in the reverse direction. The identification of the proteins that make up the classic amyloid (see Glossary) plaques and neurofibrillary tangles in Alzheimer disease cortex suggested their respective genes as sites to search for pathogenic mutations, and such mutations were subsequently found. While rare, they have been enormously instructive in attempts to develop a dynamic model of how Alzheimer disease unfolds. Thus, an understanding of the biochemical pathology preceded genetic discoveries in Alzheimer disease.

First Page Preview

View Large
First page PDF preview

Figures

Grahic Jump Location
Figure 1.
Schematic diagrams of the β-amyloid precursor proteinAPPand its principal metabolic derivatives.

The first line depicts the largest of the known β-amyloid precursor protein alternate splice forms, comprising 770 amino acids. Regions of interest are indicated at their correct relative positions. A 17-residue signal peptide occurs at the N-terminus (box with vertical lines). Two alternatively spliced exons of 56 and 19 amino acids are inserted at residue 289; the first contains a serine protease inhibitor domain of the Kunitz type (KPI). A single membrane-spanning domain (transmembrane [TM]) at amino acids 700 through 723 is indicated (dotted lines). The β-amyloid protein (β) fragment includes 28 residues just outside the membrane plus the first 12 to 14 residues of the TM domain. In the second line, the sequence within β-amyloid precursor protein that contains the β-amyloid protein and TM regions is expanded. The underlined residues represent the β-amyloid proteins 1 to 42 peptide. The green letters below the wild-type sequence indicate the currently known missense mutations identified in certain families with Alzheimer disease or hereditary cerebral hemorrhage with amyloidosis. The 3-digit numbers are codon numbers (β-amyloid precursor protein 770 isoform). In the third line, the first arrow indicates the site (after residue 687) of a cleavage by α-secretase that enables secretion of the large, soluble ectodomain of β-amyloid precursor protein (APPs-α) into the medium and retention of the 83-residue C-terminal fragment (C99) in the membrane. The C83 fragment can undergo cleavage by the protease called γ-secretase at residue 711 or residue 713 to release the p3 peptides. The fourth line depicts the alternative proteolytic cleavage after residue 671 by β-secretase that causes the secretion of the slightly truncated APP -β molecule and the retention of a 99 residue C-terminal fragment (C99). The C99 fragment can also undergo cleavage by γ-secretase to release the β-amyloid peptides. Cleavage of both C83 and C99 by γ-secretase releases the β-amyloid precursor protein intracellular domain (AICD) into the cytoplasm.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Hypothetical model of the role of presenilin in Notch and β-amyloid precursor protein processing based on current information.

The diagram shows the predicted 8 transmembrane domain topology of presenilin, which occurs principally as a cleaved heterodimer. Some Notch and β-amyloid precursor protein molecules form complexes with presenilin. Two aspartates (D) in transmembrane domains 6 and 7 of presenilin are required for the cleavages of Notch and β-amyloid precursor protein within their transmembrane domains, and these may align with the respective sites of cleavage in the 2 substrates. Presenilin directly effects these cleavages in a γ-secretase complex that contains at least 3 other membrane proteins. Several motifs are depicted in Notch: epidermal growth factor–like repeats (yellow circles), LNG (lin-Notch-glp) repeats (orange diamonds), a single transmembrane (white box), the RAM23 domain (blue square), a nuclear localization sequence (red rectangle), and 6 cdc10/ankyrin repeats (green ovals). After the putative intramembranous cleavage is mediated by presenilin, the Notch intracellular domain is released to the nucleus to activate transcription of target genes. β-Amyloid precursor protein contains the β-amyloid protein region (blue box), which is released into the lumen after sequential cleavages of β-amyloid precursor protein by β-secretase and then γ-secretase or presenilin. The released β-amyloid precursor protein intracellular domain can reach the nucleus, but its function there is undefined. APP = β-amyloid precursor protein.

Grahic Jump Location
Grahic Jump Location
Figure 3.
A hypothetical sequence of the pathogenetic steps of Alzheimer disease based on currently available evidence.

β-Amyloid protein 42 is the 42-residue form of β-amyloid. Aβ = β-amyloid protein; APP = β-amyloid precursor protein; ApoE4 = apolipoprotein E4.

Grahic Jump Location

Tables

References

Letters

NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

Submit a Comment
Submit a Comment

Summary for Patients

Clinical Slide Sets

Terms of Use

The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.

Toolkit

Buy Now

to gain full access to the content and tools.

Want to Subscribe?

Learn more about subscription options

Advertisement
Related Articles
Related Point of Care
Topic Collections
PubMed Articles
Forgot your password?
Enter your username and email address. We'll send you a reminder to the email address on record.
(Required)
(Required)