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Alzheimer's Disease: Its Origin at the Membrane, Evidence and Questions*

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Alzheimer's Disease: Its Origin at the Membrane, Evidence and Questions* Vol. 47 No. 3/2000 725–733 QUARTERLY Review Alzheimer’s disease: Its origin at the membrane, evidence and questions*. Rene Buchet1,½ and S³awomir Piku³a2 1Laboratoire de Physico-Chimie Biologique, Université Claude Bernard-Lyon 1, UFR de Chimie-Biochimie, CNRS UMR 5013, F-69622 Villeurbanne, France; 2Department of Cellular Biochemistry, M. Nencki Institute of Experimental Biology, L. Pasteura 3, 02-093 Warszawa, Poland Received: 04 July, 2000; accepted: 03 August, 2000 Key words: b-amyloid precursor protein, membrane proteases, lipid composition, membrane microdomains, Alzheimer’s disease Numerous results on membrane lipid composition from different regions of auto- psied Alzheimer’s disease brains in comparison with corresponding fractions isolated from control brains revealed significant differences in serine- and ethanolamine-con- taining glycerophospholipid as well as in glycosphingolipid content. Changes in mem- brane lipid composition are frequently accompanied by alterations in membrane flu- idity, hydrophobic mismatch, lipid signaling pathways, transient formation and disap- pearance of lipid microdomains, changes in membrane permeability to cations and variations of other membrane properties. In this review we focus on possible implica- tions of altered membrane composition on b-amyloid precursor protein (APP) and on proteolysis of APP leading eventually to the formation of neurotoxic b-amyloid (Ab) peptides, the major proteinaceous component of extracellular senile plaques, directly involved in Alzheimer’s disease pathogenesis. Alzheimer’s disease is a progressive neuro- formed by cytoskeletal protein tau in the degenerative disorder that is clinically charac- neuronal cell body, and neuropil threads in terized by the presence of extracellular senile dendrites, as well as by synapse and selective plaques, intracellular neurofibrillary tangles neuronal cell loss [1–3]. b-Amyloid (Ab) pep- *75th Anniversary of Membrane Lipid Bilayer Concept. .Work in the Authors’ laboratories is supported by a grant from C.N.R.S. (R.B.) and statutable funds from the Nencki Institute of Experimental Biology (S.P.). ½Tel.: (33 47) 243 1320; fax: (33 47) 243 1543; e-mail: [email protected] Abbreviations: Ab, b-amyloid; APP, b-amyloid precursor protein; sAPP, secreted b-amyloid precursor protein. 726 R. Buchet and S³. Piku³a 2000 tides represent the major component of senile ganization [13]. In this review, we will discuss plaques (so-called amyloid plaques) and are about possible effects of lipid compositions on generated during endoproteolysis of a large i) APP endoproteolysis and on ii) ion channel transmembrane protein, b-amyloid precursor properties of Ab peptides in relation to their protein (APP). The detailed etiopathology of neurotoxicity. Alzheimer’s disease is still unclear and is likely to be multifactorial with various genetic and environmental causes at distinct levels BASIC CHARACTERISTICS OF for each individual [4]. Several hypotheses b-AMYLOID PRECURSOR PROTEIN have been proposed to explain the degenera- tion of neurons in Alzheimer’s disease, includ- Ab peptides, the major components of amy- ing the “amyloid cascade hypothesis“ which loid plaques, are produced during endopro- states that an increased level of 42 to 43 teolysis of a large type-I transmembrane pro- amino acid long Ab peptides (due to mis-sense tein, so-called b-amyloid precursor protein mutations in the APP and presenilin genes, (APP). This protein is derived by differential age-related defects or environment) leads to splicing of a single gene transript located on aggregation of these peptides and formation the long arm of chromosome 21. In this re- of amyloid plaques, resulting in progressive spect, trisomy of chromosome 21 (Down syn- neurodegeneration [5]. In addition to this hy- drome) leads to the overexpression of APP pothesis, several factors were invoked to con- and to the formation of precocious senile tribute to the progressive neurodegenerative plaques. The predominant isoforms, APP770, disease such as: selective vulnerability of cho- APP751, and APP695 (numbers indicate the linergic neurons in the basal forebrain, mito- number of amino-acid residues in each iso- chondrial dysfunction, oxidative stress, viral form), are expressed with some tissue speci- agents, toxic material deposits, deficiency of ficity [1]. The two longer isoforms of APP, particular nutrients, overstimulation of excit- APP751 and APP770, contain a 56 amino acid atory amino acid receptors, and altered phos- long ectodomain homologous to the Kunitz pholipid metabolism [6–9]. Especially the lat- family of serine protease inhibitors. It has ter factor gained recently the attention of in- been postulated that the secreted form of APP vestigators due to the observations that the (sAPP, see next paragraph) could function as development of Alzheimer’s disease is accom- a circulating protease inhibitor [14]. In addi- panied by changes in the levels of neuronal tion, the secreted and membrane forms of membrane phospholipids: phosphatidyl- APP may be involved in neurite adhesion, serine, phosphatidylethanolamine, and phos- neurite extension via a neurotropic effect and phatidylinositol [10, 11]. In addition, Gins- may play a protective role against excitoxicity berg et al. [12] found that decreased ratio of [1]. The secondary structure of the secreted plasmalogen to nonplasmalogen ethanol- and membrane forms of APP is largely a-heli- amine glycerophospholipids in the temporal cal, since these proteins contain 40–45% of cortex of Alzheimer’s disease individuals may a-helix and only 15–20% of b-sheet structures result in membrane instability. This would fol- [15]. low the development of the so-called hydro- phobic mismatch in the membranes, i.e., the difference in length between the hydrophobic PROCESSING OF b-AMYLOID part of membrane spanning proteins, such as PRECURSOR PROTEIN APP, and the hydrophobic region of the mem- brane lipid bilayer. Such a hydrophobic mis- Newly synthesized APP matures in the se- match can strongly affect protein and lipid or- cretory pathway by the addition of O-glycosyl Vol. 47 Alzheimer’s disease and membranes 727 and N-glycosyl residues as well as tyrosine sul- pathway [16]. In the major processing path- fation in the trans-Golgi network [14]. At least way of APP, i.e., the nonamyloidogenic path- two distinct pools of APP appear to be present way, this protein is cleaved within the Ab do- in primary neuronal cultures: the major pool main (between Lys16 and Leu17; numbering of APP is characterized by a short half-life in according to the primary sequence of Ab pep- the range of 30–60 min and a minor full- tides) preventing the formation of Ab pep- length, transmembrane pool of APP by a lon- tides. During this cleavage by the protease ger half-life [4]. It has been proposed that the called a-secretase, a soluble ectodomain of major pool of APP with the rapid turnover is APP (sAPPa) is released and a 10-kDa in part secreted out of the cell in the form of C-terminal fragment (p3CT) remains within soluble APP (sAPPa), while the minor pool of the membrane (Fig. 1). This cleavage may oc- full-length APP remains at the surface of the cur in the post-Golgi compartment [14], at the neurite. The latter localization of APP is con- surface of a neuronal cell [17] or within spe- sistent with a role for this protein in the stabi- cific membrane microdomains, caveolae [18], lization of cell–matrix or cell–cell interaction suggesting that distinct pools of APP may co- [4]. Further processing of APP via the exist within the cell [4, 19]. The soluble pep- nonamyloidogenic or amyloidogenic path- tide derived from APP, sAPPa, is detected in ways is depicted in Fig. 1. APP is more likely plasma and cerebrospinal fluid and may have to be cleaved after O-glycosylation, indicating neuroprotective roles [1, 14]. In the amylo- that the cleavage of APP occurs either idogenic pathway that is a minor route, APP is throughout the Golgi complex (site of cleaved by b-secretase at the N-terminus of the glycosylation) or in compartments subse- Ab domain, producing a soluble protein quent to trans-Golgi in the APP processing (sAPPb) shorter than sAPPa and a C-terminal p3 p3CT APP A4CT A42b A40b C C C cytosol membrane g g cut a cut b cut g cut a b N N N sAPPa sAPPb Figure 1. Schematic representation of APP isoforms and their processing by a-, b- and g-secretases. APP is processed via either the nonamyloidogenic (toward the formation of less neurotoxic p3 fragment) or amyloidogenic pathways (toward the formation of more neurotoxic Ab42 or Ab40 fragments). In the nonamyloidogenic pathway a-secretase cleaves APP isoforms within the Ab domain releasing a large soluble fragments of APP (sAPPa) and a membrane-bound fragment (p3CT). Then, eventually, p3CT fragment can be cleaved by a g-secretase, releasing the C-terminal p3 peptide. In the amyloidogenic pathway, b-secretase produces the membrane-bound A4CT fragment and releases the soluble sAPPb. Further processing of the A4CT peptide by g-secretase generates the Ab40 or Ab42 peptides [1]. The filled rectangle within APP indicates the Ab42 peptide and its approximate location within the membrane bilayer. The Greek letters a, b and g beside the rectangle show the cleavage sites for the respective secretases. 728 R. Buchet and S³. Piku³a 2000 peptide residing in the membrane (A4CT). since they are good candidates for drug design The A4CT fragment is the precursor for Ab to prevent the Ab peptide formation. Al- peptides (Fig. 1). b-Secretase cleaves APP ei- though a-secretase has not been isolated yet, ther within the endocytic pathway following this protease appears to be an integral mem- reinternalization of cell-surface APP or within brane protein that is inhibited by hydroxamic the endoplasmic reticulum and Golgi. The ex- acid-based zinc metalloproteinase inhibitors istence of various sites of action of b-secretase [22]. Moreover, Vassar et al. [23] have cloned is consistent with the existence of distinct a transmembrane aspartic protease, BACE, pools of APP within the nervous system [4, which has characteristics of b-secretase.
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