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  • Review Article
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γ-Secretase, notch, Aβ and alzheimer's disease: Where do the presenilins fit in?

Nature Reviews Neuroscience volume 3, pages 281–290 (2002)Cite this article

Key Points

  • Alzheimer's disease is characterized by histological changes in the brain, including extracellular amyloid plaques that are composed of the amyloid-β peptide (Aβ), and intracellular neurofibrillary tangles that are composed of the microtubule associated protein TAU. The analysis of genes associated with inherited risk of Alzheimer's disease has indicated that increased production or decreased removal of Aβ is a key early event in the cascade that leads to these changes.

  • Aβ is derived from the amyloid precursor protein (APP), which undergoes a series of proteolytic cleavage events. The first, α-secretase event is mediated by members of the ADAM metalloproteinase family, and cleaves APP through the centre of the Aβ domain. This cleavage therefore precludes the formation of Aβ. In most cells, this is the predominant pathway for APP processing.

  • The other pathway involves two sequential cleavages of APP. The first, at the beginning of the Aβ-peptide domain, involves a membrane-bound aspartyl protease called β-secretase or BACE (β-site APP-cleaving enzyme). The second cleavage event, which clips the resulting β-stub in the centre of the transmembrane domain to generate the Aβ peptide and one or more carboxy-terminal fragments, is termed γ-secretase cleavage. The proteolytic cleavage of type 1 transmembrane proteins, such as APP, Notch, ErbB4 and Ire1p, within their hydrophobic transmembrane domains represents a novel form of regulated intramembranous proteolysis similar to that which cleaves SREBP (sterol-regulatory-element-binding protein) during the regulation of sterol metabolism.

  • Biochemical studies in cells in which the presenilin (PS) genes have been knocked out reveal that PS1 is required for and that PS2 facilitates this γ-secretase activity. In the absence of PS1, γ-secretase cleavage is significantly reduced, and in a double-knockout cell it is inhibited completely.

  • γ-Secretase cleavage of APP and the analogous S3-site cleavage of Notch generate a series of amino- and carboxy-terminal proteolytic products. Although all of the cleavage events involved in the generation of these products are presenilin-dependent, these cleavages of APP and Notch might be mediated by separate but similar pathways. The single known end-product of presenilin-dependent cleavage of Notch is the carboxy-terminal Notch intracellular domain, which derives from cleavage of Notch after residue 1743. This process is heavily dependent on the amino-acid sequence of Notch near the cleavage site. By contrast, cleavage of APP generates a series of amino-terminal fragments, including Aβ40, Aβ42 and rarer species, as well as a series of carboxy-terminal fragments, and is not dependent on the sequence of APP near these cleavage sites.

  • Some evidence has suggested that the presenilins might be either the catalytic site or a component of a multimeric γ-secretase enzyme complex: PS1 has weak sequence similarities to bacterial peptidases; transition-state analogue inhibitors of γ-secretase can be chemically cross-linked to PS1; mutation of two conserved aspartyl residues within transmembrane domains (which could be putative active-site residues of an aspartyl protease) inhibits γ-secretase cleavage; and PS1 and γ-secretase catalytic activities co-elute in purification studies.

  • But several observations do not fit easily with this hypothesis. First, there are subtle differences between the cleavage sites and sequence requirements for cleavage of APP and Notch during presenilin-mediated γ-like cleavage, so the catalytic activities might be carried out by other (possibly substrate-specific) components of the presenilin complex or by a distinct entity. In addition, mutation of both of the aspartyl residues does not completely suppress Aβ production, although it does cause accumulation of the substrates for γ-secretase cleavage (raising the possibility that PS1 is involved in trafficking substrates to or adapting substrates for the γ-secretase). Finally, although some studies using overexpressed presenilin transgenes suggest otherwise, most presenilin protein seems to be located within intracellular membranes. By contrast, most γ-like cleavage of Notch and APP seems to occur close to or after the plasmalemma (the 'spatial paradox').

Abstract

Investigations into the proteolytic processing of amyloid precursor protein (APP) have provided insights into both the pathogenesis of Alzheimer's disease and an unusual form of regulated proteolytic processing within the membrane-spanning domains of several proteins, including APP, Notch and ErbB4. Some of the enzymes responsible for α- and β-secretase cleavage have been identified, and these seem to be conventional proteolytic events. However, the molecular events that are involved in γ-secretase cleavage within the transmembrane domain of these proteins are much more complex. The presenilins and nicastrin are required for this process, but the role of the presenilins remains unclear. Although some data support the idea that the presenilins are in fact the active site of γ-secretase, other data indicate that they might have a more indirect role — for example, in transporting substrates to the correct subcellular compartments for γ-secretase cleavage.

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Figure 1: The neuropathology of Alzheimer's disease.
Figure 2: Schematic of the proteolytic events and cleavage products that are generated during the processing of APP.
Figure 3: Topology of the presenilin proteins.
Figure 4: Comparisons of proteolytic cleavage sites in APP and Notch.

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Acknowledgements

We acknowledge support from the US Public Health Service, the Metropolitan Life Foundation, the Adler Foundation, the Alzheimer's Association, the American Health Assistance Foundation, the Canadian Institutes of Health Research, the Alzheimer Society of Ontario and the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Department of Neurobiology, Center for Molecular Neurobiology, Pharmacology and Physiology, The University of Chicago, Chicago, 60637, Illinois, USA

    Sangram S. Sisodia

  2. Centre for Research in Neurodegenerative Diseases and Department of Medicine, University of Toronto, and Dept of Medicine (Neurology), Toronto Western Hospital, Toronto, M5S 3H2, Ontario, Canada

    Peter H. St George-Hyslop

Authors
  1. Sangram S. Sisodia
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Correspondence to Peter H. St George-Hyslop.

Related links

Related links

DATABASES

Entrez Protein

APH-2

GLP-1

HOP-1

LAG-1

LIN-12

SEL-12

SPE-4

FlyBase

Nicastrin

Notch

Presenilin

Su(H)

LocusLink

ApoE

APP

ATF6

BACE1

BACE2

β-catenin

δ-catenin

delta

ErbB4

ICAM5

IDE

kinesin 1

LRP1

neprilysin

nicastrin

Notch1

presenilin 1

presenilin 2

SCAP

SREBP

TACE

TAU

TrkB

OMIM

Alzheimer's disease

Down's syndrome

FURTHER INFORMATION

Encyclopedia of Life Sciences

Alzheimer disease

amyloidosis

FAD-linked presenilin missense mutations

Glossary

TYPE 1 TRANSMEMBRANE RECEPTORS

Transmembrane proteins that traverse the membrane once, with the carboxyl terminus in the cytoplasm and the amino terminus oriented towards the lumen or extracellular space.

PC12 CELLS

Neuron-like cells that are derived from a malignant neural crest tumour (a phaeochromocytoma).

HOLOPROTEIN

The full-length, native polypeptide before proteolytic cleavage events that might occur during maturation.

ARMADILLO-REPEAT PROTEINS

An extensive family of highly conserved, related proteins that contain a series of amino-acid repeat elements (called arm-repeats), and which have diverse cellular functions, including structural and signal-transduction roles. This family includes the α-, β- and γ-catenins.

RNA INTERFERENCE

(RNAi). A method by which double-stranded RNA that is encoded on an exogenous vector can be used to interfere with normal RNA processing, causing rapid degradation of the endogenous RNA and thereby precluding translation. This provides a simple way of studying the effects of the absence of a gene product in simple organisms and in cells.

DOMINANT NEGATIVE

Describes a mutant molecule that can form a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.

CSL PROTEIN

CBF1, Su(H) and LAG-1 proteins are a series of downstream transcriptional regulators that are involved in the nuclear transduction of Notch-receptor-mediated signalling events at the cell surface.

DI-ASPARTYL PROTEASE

A putative protease in which the active catalytic site contains two aspartyl residues.

TRANSITION-STATE ANALOGUE

A compound that is designed to resemble an intermediate, transition-state complex between a protease and its substrate. It is intended to inactivate the protease in a 'dead-end' complex.

SCISSILE BOND

The inter-amino-acid bond that is cleaved during proteolysis.

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Sisodia, S., St George-Hyslop, P. γ-Secretase, notch, Aβ and alzheimer's disease: Where do the presenilins fit in?. Nat Rev Neurosci 3, 281–290 (2002). https://doi.org/10.1038/nrn785

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