Biogenesis and metabolism of Alzheimer’s disease Aβ amyloid peptides

doi:10.1016/S0196-9781(02)00063-3

Peptides

Volume 23, Issue 7, July 2002, Pages 1285-1297

https://doi.org/10.1016/S0196-9781(02)00063-3 Get rights and content

Abstract

Biochemical and genetic evidence indicates the balance of biogenesis/clearance of Aβ amyloid peptides is altered in Alzheimer’s disease. Aβ is derived, by two sequential cleavages, from the receptor-like amyloid precursor protein (APP). The proteases involved are β-secretase, identified as the novel aspartyl protease BACE, and γ-secretase, a multimeric complex containing the presenilins (PS). γ-Secretase can release either Aβ40 or the more aggregating and cytotoxic Aβ42. Secreted Aβ peptides become either degraded by the metalloproteases insulin-degrading enzyme (IDE) and neprilysin or metabolized through receptor uptake mediated by apolipoprotein E. Therapeutic approaches based on secretase inhibition or amyloid clearance are currently under development.

Introduction

Alzheimer’s disease is the most common form of dementia and affects one in four individuals aged over 85. Post-mortem diagnosis includes major degeneration of the brain cortex with presence of amyloid as large extracellular plaques, perivascular deposits, and intra-neuronal fibrillary tangles. The amyloid or senile plaques are composed of Aβ peptides [94]. These peptides are proteolytically derived from a type 1 integral protein termed amyloid precursor protein (APP) [68] and contain part of the membrane-spanning domain. APP’s function remains poorly understood although it has been implicated with cell adhesion and neurite outgrowth. Whether Aβ production is physiologically important or simply represents a metabolic pathway of APP degradation is debatable [178] but increasing experimental evidence supports the amyloid cascade hypothesis [53]: accumulation and aggregation of Aβ is the primary cause of AD, inducing an inflammatory response followed by neuritic injury, hyperphosphorylation of tau protein and formation of fibrillary tangles, leading ultimately to neuronal dysfunction and cell death. Animal models which reproduce AD pathology and develop amyloid deposits show learning deficits reminiscent of those of humans affected with the disease [21]. Thus, prevention of Aβ production and accumulation is currently being evaluated as a potential therapeutic intervention for AD. We will review the current knowledge of the proteolytic processing of APP, that generates the Aβ peptides and of how these become metabolized and degraded (Fig. 1).

Section snippets

Aβ amyloid protein and Alzheimer’s disease

The presence of amyloid plaques and congophilic angiopathy in the brain cortex and hippocampus has for long been recognized as a major pathological feature of AD [2]. Isolation and chemical characterization of the amyloid plaques and vascular amyloid revealed the Aβ protein [52], [94] and led to cloning of the APP [68]. Remarkably, the APP gene locus was found on chromosome 21, and the fact that Down syndrome subjects who carry an extra copy of chromosome 21 develop AD at a very early age

Structure and putative functions of the APP

The APP gene is constituted of 18 exons that can be alternatively spliced to create 10 isoforms ranging form 563 to 770 amino acid residues [30]. Peripheral tissues express APP isoforms that contain a serine protease inhibitor insert (KPI) [71], [111], [149] and may regulate blood coagulation factors [130], [143]. Neurons express APP₆₉₅ isoform that lacks the KPI domain. Two APP gene homologues have also been identified, amyloid precursor-like proteins (APLP-1 and APLP-2) but these have little

APP is proteolytically processed near and within its transmembrane domain

Understanding the proteolytic processing events that take place near and within the APP transmembrane domain may give us clues for designing rational therapies for AD. APP ectodomain can be shed form the membrane by two alternative cleavages: α-secretase cleavage that splits Aβ domain and precludes Aβ formation, and β-secretase cleavage that exposes the amino-terminus of the Aβ peptide (Fig. 3; [41], [132]). Fragments resulting from these two cleavages remain associated with the membrane and

α-Secretase/β-secretase: two alternative routes for APP secretion

α-Secretase cleavage corresponds to the default secretory pathway and predominates in all non-neuronal cells, including mammalian cells [139], [160] and platelets [14], insect cells [10], [90], baculovirus [73], and the yeast [58], [80], [181]. It is usually considered as non-amyloidogenic because it does not produce Aβ; however, its derived product p3 [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40],

γ-Secretase cleavage: the critical step in Aβ generation

Fragments resulting from α- and β-secretase cleavage remain anchored in the membrane and may become degraded or further processed by γ-secretase to form p3 (∼3 kDa peptides derived from α-secretase cleavage) and Aβ (∼4.5 kDa products derived from β-secretase cleavage). The recovery of Aβ peptides from biological fluids and from mammalian cell cultures [133] indicated that γ-secretase cleavage is a normal cellular event. However, this constitutes a rather unusual proteolytic cleavage as it occurs

The PS are directly associated with γ-secretase cleavage

The demonstration, by our group and by others, of a direct molecular interaction between PS and APP [118], [161], [172] suggested PS would play a role in the trafficking or in the cleavage of APP. The finding of an 80% reduction in γ-secretase activity in cells derived from PS 1 (PS1) knockout mice [35] and in cells transfected with PS1 dominant negative mutants [169] proved that γ-secretase, or the γ-secretase pathway, were directly linked with PS1. PS1 knockout experiments have also unveiled

Is there an additional step in the formation of Aβ?

An intriguing question that concerns γ-secretase cleavage remains open. The γ-CTF C-terminal counterpart of Aβ that is expected to be produced by γ-secretase cleavage, has not been characterized. Recent studies have demonstrated the formation of a C-terminal product of APP released by semi-purified γ-secretase preparation in a cell-free system [96], [116]. This fragment has the expected electrophoretic mobility of γ-CTF but no N-terminal sequencing data are provided to confirm its identity. Our

Is γ-secretase cleavage abnormal in AD?

How PS and APP mutations cause abnormal production of longer Aβ isoforms has not been clarified so far. We may propose two hypotheses: either these two peptides are produced by alternative proteases (i.e. PS-associated γ-secretase/degradation mechanism involving endosomal proteases or the proteasome [26], [140]), or they are produced by a same protease acting on alternative substrate conformations. The dual protease hypothesis would be supported by reports that protease inhibitors have slightly

Aβ clearance mechansims

A considerable amount of research activity has been committed to clarifying the cellular mechanisms of Aβ formation and identifying the secretase enzymes. Relatively less effort has been aimed at understanding Aβ metabolism and degradation.

Genetic predisposition to late-onset AD has been linked to apoliprotein E (ApoE) ε4 allele [29]. The three major ApoE alleles commonly found are ε2, ε3, and ε4. Inheritance of at least one ε4 allele decreases considerably the age of AD onset. ApoE was shown

Novel therapeutic strategies for AD

Novel anti-amyloid therapies are currently being investigated. These consist in preventing amyloid formation by interfering directly with the APP secretases (either by inhibiting β- and γ-secretases, or by favoring the α-secretase pathway versus the β-secretase pathway) or in clearing the amyloid peptides by use of defibrillating agents or by immunization (Table 1).

β-Secretase candidate BACE appears to be an ideal target for drug design. Inhibitors have been described that are based on the APP

Acknowledgements

Supported by the National Health and Medical Research Council of Australia (Grant 114150).

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Biogenesis and metabolism of Alzheimer’s disease Aβ amyloid peptides

Abstract

Introduction

Section snippets

Aβ amyloid protein and Alzheimer’s disease

Structure and putative functions of the APP

APP is proteolytically processed near and within its transmembrane domain

α-Secretase/β-secretase: two alternative routes for APP secretion

γ-Secretase cleavage: the critical step in Aβ generation

The PS are directly associated with γ-secretase cleavage

Is there an additional step in the formation of Aβ?

Is γ-secretase cleavage abnormal in AD?

Aβ clearance mechansims

Novel therapeutic strategies for AD

Acknowledgements

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Alig. Z. Psychiat.

Unusual phenotypic alteration of β-amyloid precursor protein (βAPP) maturation by a new Val-715→Met βAPP-770 mutation responsible for probable early-onset Alzheimer’s disease

Proc. Natl. Acad. Sci. U.S.A.

Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition

Nat. Genet.

Aspartate mutations in presenilin and gamma-secretase inhibitors both impair Notch 1 proteolysis and nuclear translocation with relative preservation of Notch 1 signaling

J. Neurochem.

Evidence for genetic linkage of Alzheimer’s disease to chromosome 10q

Science

Regulation of APP expression, biogenesis and metabolism by extracellular matrix and cytokines

Ann. N Y Acad. Sci.

Expression of active secreted forms of human-amyloid β-protein precursor by recombinant baculovirus-infected insect cells

Proc. Natl. Acad. Sci. U.S.A.

α-2-Macroglobulin is genetically associated with Alzheimer disease

Nat. Genet.

The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein

Mol. Cell. Biol.

BACE1 is the major β-secretase for generation of Aβ peptides by neurons

Nat. Neurosci.

Protein phosphorylation regulates secretion of Alzheimer β/A4-amyloid precursor protein

Proc. Natl. Acad. Sci. U.S.A.

The multiple paradoxes of presenilins

J. Neurochem.

A learning deficit related to age and β-amyloid plaques in a mouse model of Alzheimer’s disease

Nature

Treatment with copper–zinc metal chelator markedly and rapidly inhibits β-amyloid accumulation in Alzheimer’s disease transgenic mice

Neuron

Purified recombinant insulin-degrading enzyme degrades amyloid β-protein but does not promote its oligomerization

Biochem. J.

Alzheimer’s disease: correlation of the suppression of β-amyloid peptide secretion from cultured cells with inhibition of the chymotrypsin-like activity of the proteasome