journal of Internal Medicine 1994: 235: 195-198

EDITORIAL

Alzheimer’s disease : a molecular perspective

Introduction In the past 5 years, few topics in biology and medicine have attracted as much interest as Alzheimer’s disease (AD). This has resulted in a rapidly increasing body of information regarding the aetiology of the disease which eventually may serve as a basis for a rational drug therapy against AD.

Today, AD should not be considered an idiopathic dementia but instead an amyloidosis that specifically affects the brain parenchyma and cerebromeningeal blood vessels, leading to neurodegeneration and loss of neuronal function.

The neuropathological hallmarks of AD are the neuritic plaques and neurofibrillary tangles (NFT) present in the brains of individuals suffering from the disease. Neuritic plaques consist of a core of amyloid surrounded by dead or dying neural cells and cell processes whereas NFT are interneuronal depositions of abnormal cytoskeletal proteins. However, neither of these structures are completely specific for AD as they also can be found in brains of non-demented

Fig. 1 Schematic overview of the three major amyloid precursor protein (APP) isoforms. The C- terminal regions (including the /?/A4 region) are identical in all isoforms. The APP forms with 770 and 751 amino acid residues (APP-770 and APP-751) contain protease inhibitor domains (KPI: protease inhibitor. Kunitz type) whereas the APP form with 6 9 5 amino acid residues (APP-695) has no protease inhibitor activity. The insert shows the sequence of the /?/A4 domain (bold letters) and surrounding amino acid residues. The amino acid substitutions, caused by the known APP mutations that causes familial Alzheimer’s disease (FAD), are shown underlined. P/A4 region: protease inhibitor (KPI) domain: Q 1 9 amino acid residues with unknown function.

aged individuals, but in considerably fewer numbers. Neurofibrillary tangles are also associated with other neurological diseases.

The amyloid cores of the neuritic plaques are composed almost exclusively of a peptide, approxi- mately 40 amino acids in length, that is usually referred to as PIA4. Massive deposition of P/A4 peptide is also the structural basis for the congophilic angiopathy of intracerebral and meningeal blood vessel walls that is associated with AD. The P/A4 peptide is, like most other amyloid forming proteins/ peptides, derived through proteolytic processing of a larger precursor protein. The Alzheimer amyloid precursor protein (APP) is a transmembrane protein with a long intraluminal amino-terminal portion and a short cytoplasmic carboxyl-terminal portion (Fig. 1). APP exists in three major isoforms with 695, 751 and 770 amino acids, respectively, that result from alternative splicing of the primary transcript [ l] . The gene encoding APP is located on the long arm of chromosome 2 1. Even although P/A4 peptide depositions are restricted to the brain and its blood

Transmembrane region

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APP-770

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APP-751

APP-695

SNKMDAEFRHDSGYNHHQKLVFFAEDV

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195

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196 C. NORDSTEDT et al.

pIA4 region

'Amyloidogenic' APP degradation

Secretion

Degraded pIA4 peptide Intact pIA4 peptide

Formation of senile plaques

vessels, APP is a ubiquitous protein that is found in platelets and virtually all of the nucleated cells which have been studied.

The function of APP is not yet fully understood, but the isoforms with 751 and 770 amino acid residues are very potent inhibitors of serine protease and are believed to function as inhibitors of co- agulation factor XIa.

Amyloid precursor protein is degraded by at least two separate pathways (Fig. 2): one leads to secretion of a large N-terminal fragment (also called protease nexin 11) into blood and CSF. The proteolytic cleavage that generates this fragment takes place within the P/A4 region of the APP molecule and thereby prevents amyloidogenesis. The second degradatory pathway generates intact P/A4 peptide that subse- quently may be deposited as amyloid.

Alzheimer's disease : risk factors Some individuals are more likely than others to develop AD. There is a clear hereditary component in AD. Some workers consider that up to 20% of all cases of AD are hereditary (familial).

Alzheimer's disease can be inherited as a dominant gene with a varying but often high penetrance that approaches 100% in some families. In a few families

Pig. 2 Secretory and amyloidogenic amyloid precursor protein (APP) degradation. The bulk of APP (all isoforms) is cleaved in the P/A4 region generating two fragments. One large N-terminal fragment that is secreted and a short C-terminal fragment that is degraded by the cell. In amyloidogenic degradation, APP is cleaved so that the P/A4 region is preserved intact. Some of the P/A4 peptide that is generated subsequently is accumulated as amyloid either in plack or in cerebromeningeal blood vessels.

with early-onset familial AD (FAD), the disease has been shown to co-segregate with a gene on chromo- some 2 1. It was therefore reasonable to investigate whether the APP gene, which is located on chromo- some 21, was altered in family members with the disease. These studies showed that, in some families with chromosome-2 1-linked FAD, the disease indeed co-segregates with point mutations in the APP gene [2, 31. The phenotypic changes-apart from FAD itself-that the mutations lead to on the molecular level are unknown. However, it can be speculated that the mutations that are known today, that all frame the /?/A4 domain (Fig. l), promote amyloidogenic degradation and subsequent amyloid deposition.

Down's syndrome (DS) is caused by an extra copy of chromosome 21 (trisomy 21). Virtually all indi- viduals with DS develop AD in their early forties. The 50% increase of the dose of the APP gene that trisomy 2 1 causes leads to increased levels of secreted APP in CSF, probably resulting from increased APP synthesis. The molecular basis for amyloid deposition in DS in unknown but it can be speculated that excess levels of APP in the cells saturates the 'non- amyloidogenic ' degradatory pathway causing a lar- ger than normal amount of APP to be degraded by the 'amyloidogenic' pathway.

EDITOR I AL: ALZHEIMER’S DISEASE 19 7

Recent studies have also shown that FAD can be linked to a gene on chromosome 14. The gene that is responsible for this form of FAD is a t present not known [4].

Apparently, only a minority of all cases of AD are caused by known genetic changes. Therefore, it is probable that epigenetic factors also can contribute to the pathogenesis of AD. Neuropathological studies indicate that head trauma might be such a factor. Brains from individuals that had died from acute head trauma have been shown to contain focal depositions of /?/A4 peptide that might precede formation of neuritic plaques.

Alzheimer’s disease : treatment strategies Alzheimer’s disease is characterized by severe loss of neurons and nerve terminals. It has been suggested that cholinergic neurons apparently are more vul- nerable than neurons utilizing other neurotrans- mitters. This finding has led to a therapeutic strategy aimed at increasing the levels of acetylcholine in diseased brains. Several different approaches have been employed ; amongst them : the administration of large quantities of acetylcholine precursors and/or administration of cholinesterase inhibitors capable of penetrating the blood-brain barrier and the in- hibiting acetylcholine degradation. Recent publi- cations indicate that cholinesterase inhibitors might be useful for treatment of AD because they relieve at least some of the symptoms. Another treatment strategy, aimed at inhibition of amyloidogenesis, would utilize protease inhibitors capable of inhibiting amyloidogenic APP degradation. Such drugs have not yet been clinically tested.

Future prospects In order to develop an effective treatment for AD it is necessary to have test systems that are suitable for testing large numbers of potentially useful drugs. AD research has been seriously hampered by the fact that there is no useful animal (i.e. rodent) model available because the disease apparently only affects large mammals and then only late in life. Attempts have been made to introduce human DNA (the APP gene or parts of it) into mice with the intention that these transgenic animals would develop neuro- pathological lesions similar to those associated with AD. Some promising results have indeed been re-

ported. However, this model has not yet completely reproduced the neuropathological lesions that are associated with AD.

Familial Alzheimer’s disease-associated APP gene mutations are so far the only direct biological markers available for AD diagnostics. As has been pointed out above, only a very limited number of patients and their relatives can benefit from these recent achieve- ments. As the knowledge about the genetic causes of AD is increasing steadily, it is probable that in the future genetic methods will play a more important role in diagnostics.

Modern techniques that make it possible to com- bine studies of both the imaging morphology and the function of the brain are now available. It is possible that nuclear magnetic resonance and positron emis- sion tomography in the future will be important in AD diagnostics.

The overall conclusion is that the knowledge about the cellular and molecular background of AD now has reached a level where it possibly can serve as a conceptual framework for developing a rational and effective treatment for this disease. It is therefore not improbable that in the not too distant future, effective drugs will be available for treatment of this disease.

Acknowledgements We thank Dr Erik Messamore, Department of Geri- atric Meqlicine, Karolinska Institute, for valuable discussions. C.N. is a recipient of a fellowship from The von Kantzow Foundation and The Swedish Society for Medical Research ; L. L. is a recipient of a fellowship from the Swedish Medical Research Coun- cil.

C. NORSTEDT, L. L A N N F E L T & B. W I N B L A D Alzheimer Research Centre

Department of Geriatric Medicine Kurolinska Institute

Huddincge University Hospital Huddinge

Sweden

References 1 Kang J. Lemaire HG. Unterbeck A. Salbaum M. Masters CL.

Grzeschik KH, Multhaupt G. Beyreuther K, Miiller-Hill B. The precursor of Alzheimer’s disease amyloid A 0 protein re- sembles a cell surface receptor. Nulure 1987; 325: 733-6.

2 Goate A. Chartier-Harlin M-C, Mullan M. Brown J, Crawford F, Pidani L, Giuffra L. Haynes A, Irving N, James L, Mant R,

198 C. NORDSTEDT et al.

Newton P. Rooke K, Roques P, Talbot C. Pericak-Vance M, Roses A. Williamson R, Rossor M. Quen M, Hardy J. Segregation of a missense mutation in the amyloid precursor gene with familial Alzheimers's disease. Nature 1991 : 349:

3 Mullan M. Crawford F. Axelrnan K . Houlden H. Lillius L, Winblad B. Lannfelt L. A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of /?- amyloid. Nature Genetics 1992: 1: 345-7.

4 Schallenberg GD. Bird TD, Wijsman EM. Orr HT. Anderson L.

704-6.

Nernens E et a/. Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14. Science 1992 : 258: 668-70.

Received 4 May 1993. accepted 15 July 1993.

Correspondence: Professor Bengt Winblad. Alzheimer Research Centre, Department of Geriatric Medicine, B56 Karolinska Institute, Huddinge University Hospital. S-141 86 Huddinge. Sweden.