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Revista médica de Chile

versión impresa ISSN 0034-9887

Rev. méd. Chile v.129 n.5 Santiago mayo 2001

http://dx.doi.org/10.4067/S0034-98872001000500015 

Alzheimer disease: 100 years later

Luigi Puglielli MD, Dora M Kovacs PhD

Almost 100 years since the first clinical report of a case of Alzheimer disease (AD), three early-onset and two late-onset AD genes have been identified. While rare mutations in the early-onset genes (amyloid precursor protein, and presenilins 1 and 2) lead to increased generation of specific forms of the amyloid ß protein (A,ß), common polymorphisms in the late-onset genes (apolipoprotein E and a2-macroglobulin) are thought to alter the clearance and degradation of A,ß in brain. Although definite proof for a direct link between altered A ß generation/clearance and neurodegeneration has not yet been attained, mechanism-based approaches for the therapeutic treatment of AD based on lowering levels of the potentially pathogenic Aß are currently underway. The recent discovery of the enzymes (secretases) responsible for generating Aß have paved the way for the development of such drugs and increase the prospects for successful therapeutic intervention to arrest AD neuropathogenesis (Rev Méd Chile 2001; 129: 569-75)
(Key-words: Alzheimer disease; Amyloid beta-Protein; Genetics, biochemical; Molecular biology)

Enfermedad de Alzheimer:
un siglo después

Después de transcurrido casi 100 años desde la primera publicación de un caso de enfermedad de Alzheimer (EA), se han podido identificar genes que determinan formas clínicas precoces y tardías de esta enfermedad. Mientras que ciertas mutaciones de baja frecuencia en los genes que determinan EA precoz (proteína precursora del amiloide y las presenilinas 1 y 2) llevan a una producción aumentada de formas específicas de la proteína ß amiloide beta (ßA), polimorfismos frecuentes en los genes que se asocian a EA tardía (apolipoproteína E y a2-macroglobulina) alterarían la depuración y degradación de ßA en el cerebro. Aunque todavía no existe prueba definitiva para una relación causal directa entre una producción y/o remoción alterada de ßA y neurodegeneración, las aproximaciones terapéuticas de EA están orientadas al descubrimiento de nuevas drogas que permitan disminuir los niveles patológicos de ßA. El reciente descubrimiento de las enzimas (secretasas) responsables de la generación de ßA ha abierto el camino para el desarrollo de tales drogas, aumentando las perspectivas para una intervención terapéutica más exitosa sobre la EA.

Manuscrito preparado por invitación de los encargados de la sección, Drs Marco Arrese
y Attilio Rigotti. Recibido el 25 de enero, 2001
Genetics and Aging Unit, Department of Neurology, Massachusetts General Hospital,
Harvard Medical School, Charlestown, MA, USA

In 1907, Alois Alzheimer reported the case of a middle-aged woman with memory deficits and progressive loss of cognitive abilities. Alois Alzheimer's father, also a general physician, had already described a similar case in that same woman's family. After analyzing all his father's previous records, Alois Alzheimer confirmed the existence of "strange" cases of personality changes and cognitive impairments, some of them often recurring in the same families. While performing an autopsy on that same woman, he used a newly developed silver stain to examine the brain and described what we now refer to as amyloid plaques and neurofibrillary tangles. Alois Alzheimer, therefore, not only was the first to identify amyloid in the brain of Alzheimer's disease (AD) patients, but also the first to report a possible hereditary-genetic form of the disease.

Almost 100 years later, some of the major genes involved in AD have been identified and the molecular mechanisms underlying the pathogenesis of the disease have been defined. The objective of this review is to give a general overview of the major achievements that we have witnessed. More detailed reviews on specific aspects of AD have previously been published1-6.

The genetics and biology of AD. AD represents the most common cause of dementia in the Western World and affects as many as 15 million individuals worldwide. It is characterized by progressive memory deficits, cognitive impairments and personality changes accompanied by diffuse structural abnormalities in the brain. AD is a complex and genetically heterogeneous disease and, together with other common disorders (e.g. cardiovascular disease, diabetes and cancer), is one the most common age-related diseases. Because of the shift in life expectancy we are experiencing, it is estimated that in 2050 about 25% of the population in the Western World will be over 65 years of age and one third of them will be affected by AD.

The genetics of AD is best explained by an age-dependent dichotomous model involving early-onset (<60 years) causative mutations and late-onset (>60 years) risk factors. Early-onset AD, also called familial AD (FAD), has so far been linked to mutations in the genes for the amyloid precursor protein (APP) on chromosome 217, presenilin 1 (PSEN1) on chromosome 148, and presenilin 2 (PSEN2) on chromosome 19. Together, they are thought to account for up to 40% of early-onset AD (for review, see ref. 3). Other FAD-associated genes still remain to be identified. Late-onset AD accounts for ~95% of AD cases and is associated with genetic polymorphisms that appear to operate as risk factors and/or genetic modifiers. Genetic linkage studies have already identified two such genetic risk factors: the e4 allele of the apolipoprotein gene (APOE-e4) on chromosome 1910 and a deletion polymorphism before exon 18 (18i) in the alpha2-macroglobulin gene on chromosome 1211.

The pathological and histological hallmarks of AD include extracellular protein deposits termed amyloid (or senile) plaques, neurofibrillary tangles, and amyloid angiopathy accompanied by diffuse loss of neurons and synapses in the neocortex, hippocampus and other subcortical regions of the brain. The etiologic and pathogenic events that lead to amyloid accumulation, synaptic loss and neurodegeneration in AD are not well understood.

Early-onset AD. The common pathogenic event that occurs in all forms of FAD is the abnormal accumulation of the amyloid ß-peptide (Aß). Aß is a 39-43 amino acid hydrophobic polypeptide proteolytically produced from a much larger transmembrane precursor, APP (Figure 1). APP consists of 695 to 770 residues, being APP 695, APP 751 and APP 770 the most common forms expressed in the brain5. They all originate from alternatively spliced mRNAs transcribed from a single gene. APP is a type I glycoprotein with its amino terminus on the lumenal/extracellular surface, a single ~23-residue transmembrane domain and a short cytoplasmic tail (Figure 1). The physiologic role of APP still remains elusive. The fact that the cytoplasmic domain of APP interacts with several cytosolic adaptor proteins, including FE6512, Disabled-113, X1114, the heterotrimeric Go protein15, and APP-BP116, suggests a potential role as a cell surface receptor. Nevertheless, a putative extracellular ligand has not been identified yet and APP's role as cell receptor remains only theoretical.

Most of APP is cleaved at the "a" position (Figure 1), between amino acids 16 and 17 of the Aß region, precluding the generation of Aß, while producing a soluble, extracellular large NH2-ectodomain (sAPP-a). The remaining C-terminal fragment can then be cleaved at the "g" position, in the short transmembrane domain producing a small 3-kDa Aß fragment (p3). Full-length Aß is produced by the ß/g pathway, where APP is first cleaved at the N-terminus of Aß(ß-cleavage) and then in the transmembrane domain (g-cleavage). The g-secretase usually cleaves APP either at position 40 or 42 of the Aß region generating Aß40 and Aß42, respectively (for review, see also refs. 1 and 5). Although Aß40 is more prevalent (~90% of secreted Aß), Aß42 aggregates far more rapidly into amyloid fibrils and is more toxic.


Figure 1. Schematic diagram of APP and Aß. The upper diagram depicts APP with its amino-and carboxyl-terminal domains. The single membrane-spanning domain (TM) is indicated by the vertical dashed lines. The Aß region is depicted as a black box. The two sites of glycosylation are also indicated (-CHO). The lower diagram shows the complete amino acid sequence of Aß with the sites where the a-, ß-, g40- or g42-cleavage occur.

The identification of specific mutations in APP, PS1 and PS2 has opened the door to the understanding of the molecular events involved in the pathogenesis of AD. To date 10 different FAD mutations have been reported in APP, 77 in PSEN1 and 5 in PSEN2. All the above FAD mutations are associated with a specific increase in the generation of Aß;42. Only exceptions are trisomy 21 (Down syndrome), where a third copy of the APP gene leads to an increased production of Aß and the APP "Swedish" mutation, which elevates total Aß levels. In vitro studies seem to confirm that an increase in the Aß42/Aßtotal ratio accelerates the aggregation and accumulation of Aß into amyloid fibrils leading to neurodegeneration and synaptic loss (reviewed in refs. 1-5).

Approximately 40% of the cases of FAD is associated with mutations in PSEN1 and PSEN2 (reviewed in ref. 3). Presenilins are expressed in most cell types, including neurons, and are localized to ER-Golgi like vesicles17. Immediately after synthesis, presenilin holoproteins undergo endoproteolysis generating stable N- and C-terminal fragments (reviewed in ref. 17). The constitutive proteolytic cleavage occurs in the cytoplasmic loop between the sixth and seventh predicted transmembrane domains. Steady-state levels of the N- and C-terminal fragments are tightly regulated, as overexpression of the holoprotein does not increase the levels of the fragments. The excess holoprotein is rapidly degraded through the proteasome machinery (reviewed in ref. 17). At present, neither the identity of the protease that cleaves presenilin holoproteins nor the physiological significance of proteolysis is known. It must be noted that most FAD-linked mutations of presenilins do not affect endoproteolysis and that endoproteolysis itself is not required for the pathogenic function of mutant presenilins in elevating the levels of Aß42 (reviewed in refs. 17 and 18). The physiologic role of presenilins is still unknown. Disruption ("knock out") of the PS1 gene in mice results in a severe phenotype, characterized by late embryonic lethality, disturbed somitogenesis, cranial hemorrhage, underdevelopment of the subventricular zone of the brain, midline closure deficiencies, and a neuronal migration disorder very similar to human lissencephaly type II19-22. In contrast, PS2 "knock out" mice are viable and fertile and develop only a mild pulmonary fibrosis and hemorrhage with age23. The above phenotypes in PS1 and PS2 "knock out" mice are caused by a defect in the processing of Notch, a cell surface-bound transcription factor, which regulates several fate decisions during embryogenesis, hematopoiesis, and neuronal stem cell differentiation (for review, see ref. 24). In fact, besides their role in AD, presenilins are also required for the proteolytic cleavage of the transmembrane domain of the Notch protein17,18,24. Upon cleavage, the Notch intracellular domain is released from the plasma membrane and translocates to the nucleus. Presenilins also seem to interact with many proteins involved in different basic cellular events, from cell adhesion to signal transduction, vesicular transport, protein quality control and regulation of intracellular calcium deposits (for review, see ref. 17). All but two presenilin FAD mutations are missense mutations, which occur in residues that are conserved between the two proteins and result in a single amino acid change (reviewed in refs. 17 and 18). They are all dispersed along the protein sequence with most of them occurring within the second and sixth predicted transmembrane domains (for review, see ref. 18). The possibility that misfolding of presenilins generated by the above mutations would be the primary cause of the increased production of Aß42 has been a common thought for many years but it has never been definitively demonstrated. The past few years have seen the emerging of several reports indicating that presenilins are the g-secretase or act as cofactor of the g-secretase (for review, see ref. 25). Even if general agreement on the function of presenilins is still lacking, chemical inhibitors of g-secretase activity bind presenilins and are under strict scrutiny as possible therapeutic tools26.

Late-onset AD. Genetic linkage studies have brought the attention to specific polymorphisms which, even if not directly required for the development of the disease, could act as risk factors in the general population. Specifically, two of such polymorphisms, the APOE-e4 allele and the 18i deletion in the alpha2-macroglobulin gene have emerged as the most powerful risk factors for late-onset AD. ApoE is one of the major lipoproteins and represents the principal cholesterol carrier in the brain. In humans, there are three common alleles of ApoE: e2, e3 and e4. The protein isoforms produced by these alleles only differ in the amino acids at position 112 or 158 of the protein sequence: E2 (cys112, cys158), E3 (cys112, arg158 ), which is the most common, and E4 (arg112 , arg158). The mechanism(s) underlying the association between AD and ApoE-e4 remains undefined. Disruption of the APOE gene in transgenic mice overexpressing the V717F human APP (APPV717I±), a mouse model for AD, inhibits the accumulation of Aß immunoreactive deposits27. Overexpression of the mouse APOE gene in the above APPV717I± background increases28 while overexpression of the human APOE gene reduces29 the deposition of ß-amyloid. The reason for such different behavior of mouse and human ApoE is not clear. Even if they are ~70% identical at the protein levels, they have different effects on plasma lipoprotein metabolism. It may be possible that different affinities for their ligands, including cholesterol and Aß, or for the cell surface receptor in the brain, the low density lipoprotein receptor related protein (LRP), are responsible for such different behavior.

Alpha2-macroglobulin is a soluble glycoprotein composed of four identical 180-kDa subunits. It binds to several ligands including virtually all proteases circulating in the plasma and the extracellular milieu (for review, see ref. 30). After binding to its ligand, alpha2-macroglobulin undergoes complex conformational changes that allow it to interact with specific cell surface receptors. The complex alpha2-macroglobulin-ligand-receptor is then internalized and both alpha2-macroglobulin and its ligand are degraded in the lysosomal compartment. The fact that both ApoE and alpha2-macroglobulin bind Aß in in vitro assays has suggested that they might be involved in the clearance of Aß amyloid from the brain. Indeed, early experiments have shown that both ApoE4 and alpha2-macroglobulin bind to LRP and mediate Aß internalization31-34. However, recent studies have also shown that Aß internalization is not followed by its degradation. Instead, Aß aggregates in the endocytic compartment and is secreted again in the fibrillar and more toxic form35,36. Even if their precise role in the pathogenesis of AD still remains to be clarified, both the APOE-e4 allele and the 18i deletion in the alpha2-macroglobulin gene are the first members of a probably large set of common population polymorphisms contributing to age-related risk for late-onset AD.

Theraphy of AD. According to the amyloid cascade hypothesis, the pharmacological inhibition of Aß production will inhibit the formation of amyloid plaques and thus arrest or reverse the pathogenesis of AD. Because Aß production is dependent on the activity of the ß- and g-secretases, identification of the proteins responsible for these activities has been a major goal of the AD research. After almost twenty years of intense investigation, four independent groups have recently succeeded in identifying and cloning the ß-secretase, renamed BACE, for ß-site APP cleaving enzyme37-40. BACE, a ~70-kDa membrane protein that belongs to a new family of aspartyl proteases has all the characteristics of the ß-secretase, including the fact that it directly regulates APP cleavage at the ß-position (for review, see refs. 41 and 42). In fact, overexpression of BACE increases ß-secretase cleavage products while antisense inhibition of BACE decreases ß-secretase cleavage products. The discovery of BACE as ß-secretase will facilitate the prospects for the development of potential AD therapeutics. The initial reports showing that BACE does not seem to be involved in the regulation of other fundamental pathways encourage to think that inhibition of BACE activity will not generate important side effects. Final proof will come only after the generation of BACE "knock out" mice. Efforts are under way to fully elucidate the structure of the BACE active site with the prospect of designing specific competitive inhibitors. The g-secretase has not yet been identified, although some evidence points toward the presenilins themselves acting as g-secretase25. Even if the presenilins are not the g-secretases themselves, their presence is necessary for Aß production. Compounds that inhibit either BACE or presenilin activity are currently being intensely investigated for a mechanism-based therapy of AD. The fact that presenilins are also involved in Notch cleavage rises the possibility that presenilins inhibitors may also affect Notch activity. Whether Notch signaling is required in complete differentiated neurons remains to be analyzed.

A different approach to AD therapy would be through the clearance of extracellular Aß. Very recently, Schenk et al43 have shown that immunization with Aß inhibits the formation of amyloid plaques and the associated dystrophic neurites in a mouse model of AD. Even if immunization protects against Aß deposition, it is not clear whether such a treatment could also help to remove already formed Aß aggregates (plaques) and whether that would generate an improvement in the cognitive functions of already diagnosed AD patients. Clinical trials are now in progress assessing the effect of Aß immunization on patients affected by AD.

CONCLUSIONS

The years to come will witness the identification of additional genes involved in early- and late-onset AD. They will help us to completely understand the molecular events involved in the pathogenesis of AD and to develop more effective strategies for the treatment and prevention of the disease. It is likely that, in the future, individuals will be offered a specific risk-assessment profile to determine their probability for developing AD. Such assessment, probably very similar to that already widely used for atherosclerosis, will determine specific therapies to follow for each individual case.

Correspondencia a: Dora M. Kovacs, PhD (Genetics and Aging Unit). Department of Neurology, Massachusetts General Hospital. Harvard Medical School. Bldg. 149, 13 th Street, Charlestown, MA, USA. Fax: (617) 726-5677.
E-mail: kovacs@helix.mgh.harvard.edu

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