The cell biology of Alzheimer's disease: uncovering the secrets of secretases

doi:10.1016/S0959-4388(00)00253-1

Current Opinion in Neurobiology

Volume 11, Issue 5, 1 October 2001, Pages 585-590

https://doi.org/10.1016/S0959-4388(00)00253-1 Get rights and content

Abstract

Progress has been made in characterizing the secretases involved in endoproteolytic processing of the β-amyloid precursor protein — the precursor of the amyloid β-peptide (Aβ), which is the main constituent of amyloid plaques that form in the brains of patients with Alzheimer's disease. It is now thought that Aβ is pivotal in the pathogenesis of Alzheimer's disease, and that reducing brain Aβ levels may help to treat or prevent the disease. Two essential factors for the proteolytic generation of Aβ have been identified, β-secretase and the presenilins, which might aid the design of drugs against this disease.

Introduction

Alzheimer's disease (AD) is the most common dementia in the world. Pathologically, the disease is characterized by the accumulation of amyloid plaques in the brain parenchyma [1]. The main components of these plaques are the amyloid β-peptides, Aβ40 and Aβ42, which contain 40 and 42 amino acids, respectively, and appear to be toxic to neurons [2].

Mutations causing autosomal-dominant forms of familial AD (FAD) have been found within the β-amyloid precursor protein (β-APP) gene itself and also in the genes encoding the homologous presenilin (PS) proteins PS1 and PS2 [3]. Whereas FAD mutations in the genes for β-APP and PS2 are very rare, more than 80 mutations have now been described for PS1. Notably, all FAD-associated mutations in these three genes lead to increased production of either total Aβ (Aβ40 and Aβ42) or only Aβ42 [4]. The elongated species aggregates significantly faster than the more abundant Aβ40 5., 6., and therefore seems to be a critical factor in the pathogenesis of AD.

Aβ is generated from β-APP by endoproteolytic processing involving sequential cleavages by β- and γ-secretase [7]. The name secretase reflects the fact that their substrates are liberated from the membrane and are then found in extracellular fluids. The initial cleavage of β-APP by β-secretase generates a membrane-bound carboxyl (C)-terminal fragment (CTF-β) starting at the Asp1 amino (N)-terminus of the Aβ domain (Fig. 1a). Subsequently, γ-secretase mediates the apparently intramembraneous cleavage of CTF-β resulting in the liberation of Aβ (Fig. 1a).

In an alternative pathway, β-APP can be cleaved by α-secretase in the center of the Aβ domain, thereby inhibiting generation of Aβ (Fig. 1a). Two related metalloproteases of the ADAM (a disintegrin and metalloprotease) family, ADAM-10 and ADAM-17, also termed TACE (tumor necrosis factor-α converting enzyme), might exert α-secretase activity 8., 9.. As α-secretase does not contribute to the generation of Aβ, in this review we describe exclusively recent discoveries concerning the cell biology of the β- and γ-secretases.

Section snippets

β-Secretase mediates the initial amyloidogenic cut in an acidic subcellular compartment

The initial cleavage of β-APP between the methionine–asparatate bond at the N-terminus of the Aβ domain is catalyzed by β-secretase, which was identified recently by several independent approaches, and was termed BACE (for β-APP cleaving enzyme), asp2 or memapsin2 10••., 11••., 12••., 13••., 14••.. BACE shares 55% homology with a second enzyme called BACE-2. Both enzymes contain the two characteristic D(T/S)G(T/S) motifs of aspartyl proteases, which form the catalytic site, and share

Presenilins are required for γ-secretase cleavage of β-APP and Notch

The β-APP C-terminal stub generated by β-secretase (CTF-β) can be processed further by γ-secretase to produce Aβ (Fig. 1a). Pharmacological inhibition of γ-secretase suggests that this enzyme is an aspartyl protease and accumulating evidence shows that PSs contain the catalytic site of γ-secretase activity [7]. A fundamental function of PSs in γ-secretase cleavage of β-APP is demonstrated by the finding that cells derived from PS1/PS2 double-knockout mice lack γ-secretase activity 29•., 30•..

Where do β-APP and secretases meet for amyloidogenesis?

APP is a type I transmembrane protein, which is transported from the ER to the cell surface through the secretory pathway [45]. From the plasma membrane, β-APP can be re-internalized into endosomal/lysosomal compartments through classical clathrin-coated pits 46., 47., dependent on tyrosine-containing signals in its cytoplasmic domain 48., 49.. From there, β-APP either recycles back to the cell surface 50., 51. or is further transported to lysosomes for its final degradation 49., 50., 51..

Conclusions and future perspectives

On the basis of the cellular mechanisms underlying the generation of Aβ, and specifically from the identification of BACE as the main β-secretase activity and PSs as essential components of the γ-secretase complex, the pharmacological inhibition of these secretase activities seems to be a very promising approach to slow down or even to prevent the progression of AD. In fact, clinical phase 1 trials with γ-secretase inhibitors are currently on the way and will hopefully result in benefits for AD

Update

Recently, several studies demonstrate the production of an intracellular CTF of β-APP 64., 65., 66. resulting from γ-secretase cleavage, which, in analogy to NICD, is referred to as AICD (APP intracellular domain; Fig. 2). Surprisingly, sequencing reveals that its N-terminus does not correspond to the expected γ-secretase cleavage after amino acids 40 or 42 of the Aβ domain 65., 66.. Instead, cleavage occurs between amino acids 49 and 50, close to the cytoplasmic side of the transmembrane

Acknowledgements

The authors thank the members of the laboratory for many fruitful discussions and critically reading the manuscript. We apologize to the authors of many articles that we could not cite because of space constraints. The work of the laboratory for Alzheimerand Parkinson's disease is supported by grants from the Deutsche Forschungsgemeinschaft, the European Union, the BMFT and Boehringer Ingelheim KG.

References and recommended reading

Papers of particular interest, published within the annual period of review,have been highlighted as:

• of special interest
•• of outstanding interest

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ReviewThe cell biology of Alzheimer's disease: uncovering the secrets of secretases

Abstract

Introduction

Section snippets

β-Secretase mediates the initial amyloidogenic cut in an acidic subcellular compartment

Presenilins are required for γ-secretase cleavage of β-APP and Notch

Where do β-APP and secretases meet for amyloidogenesis?

Conclusions and future perspectives

Update

Acknowledgements

References and recommended reading

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Mol Cell Neurosci

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Neuron

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Alzheimer's disease: genes, proteins, and therapy

Physiol Rev

Molecular genetics of Alzheimer's disease: the role of β-amyloid and the presenilins

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Amyloid diseases: abnormal protein aggregation in neurodegeneration

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Nat Rev Mol Cell Biol

Review
The cell biology of Alzheimer's disease: uncovering the secrets of secretases