Christine van Broeckhoven1
Neurodegenerative brain diseases, including dementias, are common diseases among elderly people, and their population frequency is increasing rapidly because people are living longer due to high quality health care systems. Predictions indicate that in 2030 at least one in four people in Western European countries will be 65 years or older. In this age group, people are at high risk for neurodegenerative dementias such as Alzheimer's disease (AD), with risk increasing with age to as high as 20% for those 85 years. Neurodegenerative brain diseases or cerebral prote(in)opathies have in common the presence of inclusion bodies containing abnormal protein aggregates. These protein depositions in specified brain regions occur within neurons or in the brain parenchyma and are commonly used as pathological hallmarks in morphological diagnosis of demented patients at autopsy. In AD, the major protein aggregates are found in parenchymal senile plaques and intraneuronal neurofibrillary tangles. The major constituents of these pathological protein aggregates have been identified for most neurodegenerative brain diseases, and the cerebral proteopathy is often nicknamed accordingly, e.g., tauopathy in cases of tau aggregates, as in frontotemporal dementia (FTD; Rademakers et al. 2004). In AD, the tauopathy consists of cytoplasmic neurofibrillary tangles and is always linked to the presence of p amyloid (Ap) in senile plaques. The Ap can also be found without concurrent tauopathy in patients with cerebral amyloid angiopathy (CAA), such as Dutch amyloidosis or hereditary cerebral hemorrhages with amyloidosis Dutch type (HCHWAD; Maat-Schieman et al. 2005; Van Broeckhoven et al. 1990). These observations suggest that Ap and tau are part of a cerebral proteopathy spectrum ranging from CAA through AD to FTD, linking these dementia phenotypes to a common molecular pathway of neurodegeneration (Dermaut et al. 2005).
AD is the most common subtype of neurodegenerative dementias, affecting nearly 70% of dementia patients, followedby FTD, which in the age group below 65 years comprises 12-20% of patients (Dermaut and Van Broeckhoven 2002). They are multifacto-rial diseases with both genetic and environmental factors contributing to expression of disease. Genetic factors are strongest in young patients, and in this group one can observe families in which the disease is inherited from generation to generation as an autosomal dominant trait (Martin et al. 1991; Cruts and Van Broeckhoven 1998a). Since the beginning of the 1980s, these families have been the subjects of molecular genetic studies aiming at identifying the underlying disease genes using the positional cloning
1 Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders In-teruniversity Institute for Biotechnology and Laboratory of Neurogenetics, Institute BornBunge at University of Antwerp, Antwerpen, Belgium strategy. For AD, this approach resulted in the identification of three genes coding for the amyloid precursor protein (APP) andthepresenilin 1 (PSEN1) and 2 (PSEN2) genes (Goate et al. 1991; Sherrington et al. 1995; Levy-Lahad et al. 1995a) and, for FTD, in the microtubule associated protein tau gene (MAPT; Hutton et al. 1998). Mutations in APP were also identified in Dutch amyloidosis (Van Broeckhoven et al. 1990; Levy et al. 1990; Bakker et al. 1991). Retrospectively, it is interesting that APP and MAPT are coding for the culprit protein underlying the proteopathies of AD, CAA (amyloidosis) and FTD (tauopathy). Mutations in these genes have been identified in families worldwide; however, their overall number and relative contribution to risk of disease are very low. In families segregating these mutations, the patients are at high risk, since most of these mutations are highly penetrant and can be used for molecular diagnostic testing. Nevertheless, the identifications of the inclusion proteins and subsequent mutations in their genes in dementia patients have been milestones in dementia research, since they provided entry points to the underlying biological pathways. It is now generally accepted that, because of the mutation, the protein changes configuration, making it more prone to aggregation and deposition, leading to the formation of the characteristic pathological lesions such as senile plaques in AD and tau aggregates in FTD. The fundamental basis for the origin and formation of the protein aggregates still remains largely unknown. Nevertheless, much research is being conducted aiming at developing novel therapeutic strategies based on prevention, degradation or clearance of these protein aggregates from brain.
Only < 1% of AD patients have early-onset (< 65 years) of disease, and around 60% of these patients have a positive family history with at least one first-degree relative demented (Ott et al. 1995; van Duijn et al. 1991). Approximately 10% of familial early-onset patients have autosomal dominant inheritance of AD, with a mean onset age that is characteristic for an individual family (Martin et al. 1991). To date, 190 different mutations in APP (N = 25; 17.6%), PSEN1 (N = 155; 78%) and PSEN2 (N = 10; 4.5%) together explain AD in 404 families worldwide (Cruts and Van Broeckhoven 1998b; AD&FTD Mutation Database http://www.molgen.ua.ac.be/ADMutations). All mutation carriers presented with classical AD with abundant senile plaques and neurofibrillary tangles. In a Dutch population-based study of early-onset AD, mutations in these three genes explained 5% overall, 10% of familial and 20% of autosomal dominant early-onset AD (van Duijn et al. 1991; Cruts et al. 1998), indicating that other genes were yet to be found for early-onset AD. We recently reported a novel locus in a Dutch early-onset AD family at 7q36, but the underlying gene remains to be found (Rademakers et al. 2005). The majority of mutations are missense mutations, except in the case of APP, where duplications have recently been reported in 8-10% of autosomal dominant AD families (Rovelet-Lecrux et al. 2006; Sleegers et al., in press). Mutations have also been identified in the APP proximal promoter that increased APP transcriptional activity nearly two-fold (Theuns et al. 2006; Brouwers et al., in press). Mutations in APP, PSEN1 and PSEN2 consistently elevate the Aß42/Aß40 ratio, with Aß42 having an increased propensity to aggregate and deposit in senile plaques (Suzuki et al. 1994; Scheuner et al. 1996; De Jonghe et al. 1998; Kumar-Singh et al. 2006b), making APP processing central in the etiology of AD. While APP mutations cause AD by a Aß42-driven gain-of-function, mutations in PSEN have recentlybeen shown to produce a loss-of-function of y-secretase activity (Bentahir et al. 2006; Kumar-Singh et al. 2006b). PSENs harbor the catalytic site of the y-secretase complex that cleaves APP just outside the C-terminal site
The genetic Alzheimer-frontotemporal dementia spectrum 239
of Ap (Marjaux et al. 2004). The loss-of-function hypothesis is in line with our previous genetic studies identifying promoter variants in PSEN1 that decreased expression and consequently increased risk for early-onset AD (van Duijn et al. 1999; Theuns et al. 2000, 2003).
AD mutations have been identified in APP and PSEN that are associated with a very strong CAA component (Hendriks et al. 1992; Dermaut et al. 2001). The Flemish APP692 mutation, Ala692Gly, located within the Ap sequence close to the a-secretase site, was identified in a Dutch family that presented clinically with either hemorrhages or dementia as first symptoms (Hendriks et al. 1992) and showed pathologically an extensive Ap load in both cored plaques and vessel walls (Cras et al. 1998; Kumar-Singh et al. 2002). Our studies of Flemish AD indicated that the altered biological properties of Flemish APP and Ap (De Jonghe et al. 1998) facilitated progressive Ap deposition in vascular walls, causing strokes and the formation of dense-core senile plaques (Kumar-Singh et al. 2002). Of interest is that we observed the same degree of CAA as in Flemish APP692 in AD patients carrying the PSEN1 Leu282Val mutation and presenting with typical AD without strokes or stroke-like episodes (Dermaut et al. 2001). Together, these data suggest that, like the dense-cored neuritic plaques, CAA might represent a pathogenic lesion that contributes significantly to the progressive neurodegeneration occurring in AD.
A positive family history of dementia is present in 38-50% of FTD patients, and in the majority of FTD families the disease is inherited in an autosomal dominant manner. Genetic studies have identified mutations in MAPT in families linked to 17q21 (Hutton et al. 1998). To date, 40 different MAPT mutations have been identified in 113 dementia families worldwide (Rademakers et al. 2004; AD&FTD Mutation Database: http://www.molgen.ua.ac.be/ADMutations). MAPT mutations are missense mutations mainly affecting microtubule binding domains or splice site mutations enhancing exon 10 splicing and resulting in abnormal preponderance of 4-repeat over 3-repeat tau. It has been estimated that MAPT mutations explain 5 to 20% of FTD in general, and 10 to 43% of familial FTD. Neuropathologically, MAPT mutation carriers are characterized by intraneuronal and/or glial tau-positive inclusions (tauopathy) ranging from AD-like neurofibrillary tangles to ovoid Pick bodies, the pathological hallmark of Pick's disease (Lee et al. 2001). Some mutations in MAPT, like Arg406Trp, cause hereditary tauopathy though presenting clinically with AD (Rademakers et al. 2003). Interestingly, PSEN1 mutations have also been associated with familial FTD (Raux et al. 2000; Tang-Wai et al. 2002; Dermaut et al. 2004). The mutation we reported, Gly183Val, was observed in a familial FTD patient with Pick-type tauopathy in the absence of extracellular -amyloid deposits. The functional details of the pathogenic role of PSEN1 mutations in FTD remain obscure; however, in vitro study of another FTD-related PSEN1 mutation, insArg352 (Tang-Wai et al. 2002), has shown that it behaves as a loss-of-function mutation because of its inability to process APP into Ap peptides (Amtul et al. 2002).
More recent genetic and clinicopathologic studies, however, demonstrated that the majority of FTD patients could not be explained by MAPT mutations and lacked tau pathology (tau-negative FTD). Surprisingly, several tau-negative FTD families showed conclusive linkage to the same region at 17q21 that contains MAPT (Rademakers et al. 2004). The neuropathology in these families has been described as either "dementia lacking distinctive histopathology" (DLDH; Lendon et al. 1998) or "FTD with tau negative and ubiquitin positive inclusions" (FTDU; Rosso et al. 2001; Rademakers et al.
2002; van der Zee et al. 2006; Mackenzie et al. 2006; Pirici et al. 2006). In one Dutch family, 1083, we reduced the candidate region for FTDU to a 4.8 cM interval (Rademak-ers et al. 2002). We excluded mutations in MAPT by genomic resequencing of 138.5 kb in 17q21-linked FTDU patients (Cruts et al. 2005) as well as complex genomic rearrangements in the MAPT region using stretched chromosome FISH (Gijselinck et al. 2006). All together, these data suggested that FTDU linked to 17q21 was independent of MAPT and most likely resulted from mutations in another gene within the linked chromosomal region at 17q21. Subsequent screening of candidate genes identified null allele mutations in the gene coding for progranulin (PGRN) that lead to partial loss of PGRN protein (Baker et al. 2006a; Cruts et al. 2006a). These data indicated that PGRN growth factor activity has an important role in neuronal survival in FTD, however, the exact disease mechanism remains to be elucidated. Of interest though is that in our hands mutations in PGRN were a more frequent cause of FTD than MAPT mutations underpinning an important role for PGRN in FTD. (Gijselinck et al. 2006). All together, these data suggest that FTDU linked to 17q21 is independent of MAPT and most likely results from mutations in another gene within the region.
In conclusion, careful genotype-proteotype-phenotype correlative studies, including molecular genetic, biochemical, neuropathological and clinical investigations of inherited early-onset forms of AD and FTD, have been instrumental in defining the complete phenotypic spectrum associated with APP, PSEN and MAPT mutations and have significantly advanced our biological understanding of these diseases (Dermaut et al. 2005). Also, recent findings showed that AD and FTD not only share important clinical and neuropathological features but are also etiologically linked at the molecular genetic level, implying that these disorders are part of a genetically interconnected spectrum of neurodegenerative brain disorders.
Acknowledgements. The author's research is supported by the Special Research Fund of the University of Antwerp, the Fund for Scientific Research Flanders (FWO-F), the Interuniversity Attraction Poles (IUAP) program P5/19 of the Belgian Science Policy Office (BELSPO), the International Alzheimer Research Foundation (IARF), Belgium; the Alzheimer Association USA, and the EU contract LSHM-CT-2003-503330 (APOPIS).
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