Current and future implications of basic and translational research on amyloid-ß peptide production and removal pathways.

Inherited variants in multiple different genes are associated with increased risk for Alzheimer's disease (AD). In many of these genes, the inherited variants alter some aspect of the production or clearance of the neurotoxic amyloid ß-peptide (Aß). Thus missense, splice site or duplication mutants in the presenilin 1 (PS1), presenilin 2 (PS2) or the amyloid precursor protein (APP) genes, which alter the levels or shift the balance of Aß produced, are associated with rare, highly penetrant autosomal dominant forms of Familial Alzheimer's Disease (FAD). Similarly, the more prevalent late-onset forms of AD are associated with both coding and non-coding variants in genes such as SORL1, PICALM and ABCA7 that affect the production and clearance of Aß. This review summarises some of the recent molecular and structural work on the role of these genes and the proteins coded by them in the biology of Aß. We also briefly outline how the emerging knowledge about the pathways involved in Aß generation and clearance can be potentially targeted therapeutically. This article is part of Special Issue entitled "Neuronal Protein".

Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model.

Latrepirdine (Dimebon) is a pro-neurogenic, antihistaminic compound that has yielded mixed results in clinical trials of mild to moderate Alzheimer's disease, with a dramatically positive outcome in a Russian clinical trial that was unconfirmed in a replication trial in the United States. We sought to determine whether latrepirdine (LAT)-stimulated amyloid precursor protein (APP) catabolism is at least partially attributable to regulation of macroautophagy, a highly conserved protein catabolism pathway that is known to be impaired in brains of patients with Alzheimer's disease (AD). We utilized several mammalian cellular models to determine whether LAT regulates mammalian target of rapamycin (mTOR) and Atg5-dependent autophagy. Male TgCRND8 mice were chronically administered LAT prior to behavior analysis in the cued and contextual fear conditioning paradigm, as well as immunohistological and biochemical analysis of AD-related neuropathology. Treatment of cultured mammalian cells with LAT led to enhanced mTOR- and Atg5-dependent autophagy. Latrepirdine treatment of TgCRND8 transgenic mice was associated with improved learning behavior and with a reduction in accumulation of Aß42 and α-synuclein. We conclude that LAT possesses pro-autophagic properties in addition to the previously reported pro-neurogenic properties, both of which are potentially relevant to the treatment and/or prevention of neurodegenerative diseases. We suggest that elucidation of the molecular mechanism(s) underlying LAT effects on neurogenesis, autophagy and behavior might warranty the further study of LAT as a potentially viable lead compound that might yield more consistent clinical benefit following the optimization of its pro-neurogenic, pro-autophagic and/or pro-cognitive activities.

The effects of APOE and tau gene variability on risk of frontotemporal dementia.

Frontotemporal dementia (FTD) is a complex dementing syndrome whose genetic/non genetic risk factors are mostly unknown. Aim of the present work was to investigate whether APOE and/or tau gene variability does affect the risk of FTD. A sample of FTD cases (sporadic: n = 54; familial: n = 46, one subject per family) was collected in a genetically homogeneous population (Calabria, southern Italy) and analyzed in comparison with an age- and sex-matched control group (n = 180) extracted from the same population. Logistic regression analysis showed that APOE gene variability affects the probability of disease, with allele epsilon4 increasing (exp(beta1) = 2.68 with [1.51-4.76] 95% confidence interval; p = 0.001) and allele epsilon2 decreasing (exp(beta1) = 0.28 with [0.12-0.66] 95% confidence interval; p = 0.003) the risk of FTD. On the contrary, tau gene variability was ineffectual (exp(beta1) non significantly different from 1 for either H1 or H2 haplotypes), although a small effect was observed by the H1 haplotype in increasing the protective effect of the epsilon2 allele (p = 0.007).

[Familial fronto-temporal dementia with brain stem ubiquitin-positive neuronal inclusions]. / Démence fronto-temporale familiale avec inclusions marquées par l'anti-ubiquitine dans le tronc cérébral.

INTRODUCTION: Fronto-temporal dementias (FTD) were described a century ago on the macroscopic basis of frontal and/or temporal lobe atrophy. Progress in neuropathology, immunohistochemistry, biochemistry and genetics has since shown that they are heterogeneous entities, encompassing many different diseases with similar clinical presentations. A few, such as tauopathies due to mutations of the gene coding for tau protein (MAPtau form a well-defined group. Definition and grouping of other types of FTD is still problematic. MATERIAL AND METHOD: We studied a family where the mother and 4/8 children were affected with FTD. Clinical presentation was typical of FTD. Onset was ill-defined with early (at age 40 years or less) personality changes. The clinical course was protracted (about 30 years). For a long period, the patients were able to live in the community in spite of obvious signs such as hyperorality and loss of verbal initiative; operative orientation as to place was preserved for a long time: a mute patient was still able to drive. Signs of extrapyramidal or motoneuron involvement were not observed. RESULTS: The genetic study failed to detect any mutation in MAPtau; the lod score for flanking markers was positive but not significant. Biochemical study showed no qualitative abnormality in tau protein. Neuropathological study of one affected subject showed brain atrophy (962 g), with elective frontal lobe involvement. Cortical nerve cell loss was more marked in superficial layers and in frontal areas; glia was inconspicuous; pseudolaminar spongiosis was present in the more severely affected zones. No argentophilic "Pick bodies" were seen; ubiquitin-positive, tau-negative round inclusions were present in the cytoplasm of fascia dentata neurones. "Tangles" were mostly restricted to the entorhinal cortex, partly correlated with tau immunoreactivity, but better with ubiquitin immunoreactivity. Large, ovoid or reniform, moderately dense, spongy, granular or filamentous argentophilic cytoplasmic nerve cell inclusions were observed. They were ubiquitin-positive, but did not react with other antibodies, particularly anti-tau. They were present in swollen nerve cells in the deeper cortical layers but were most conspicuous in the brain stem: in the magnocellular reticular nuclei (e.g. nucleus centralis pontis), in the pes pontis, in the inferior olive and in motor nuclei, especially in the trigeminal motor nucleus. They were not associated with nerve cell loss, atrophy nor pycnosis. Cerebellar relay nuclei neurones were swollen, and their cytoplasm contained argentophilic filaments. CONCLUSION: In our opinion, "ubiquitinopathy" would be non-specific and "Motor Neuron Disease-Inclusion Dementia" (MNDID) would not be satisfactory as a diagnosis for the present cases of FTD. Hopefully, progress in genetics may allow a causal, and thence definitive, classification.

A new SPG4 mutation in a variant form of spastic paraplegia with congenital arachnoid cysts.

The clinical and genetic findings are described for 16 patients from a large Italian family with a variant form of hereditary spastic paraplegia and congenital arachnoid cysts inherited as an autosomal dominant trait. A molecular study has revealed a novel missense mutation, T614I, in exon 17 of SPG4, which may play a role in both focal cortical dysgenesis and neurodegeneration of the motor neurons in the corticospinal tract.

PS1 Alzheimer's disease family with spastic paraplegia: the search for a gene modifier.

PS1 mutations are associated with classic Alzheimer's disease (AD); however, some families develop AD and spastic paraplegia (SP) with brain pathology characterized by Abeta cotton wool plaques. The authors report a variant AD family with the E280Q PS1 mutation. The fact that the same PS1 mutation can be found in patients with either variant or classic AD argues in favor of the presence of a genetic modifier. The authors have excluded that this modifier effect originates from coding sequence variations in three SP genes or from a second mutation in the other AD genes.

Clinical and genetic study of a large Italian family linked to SPG12 locus.

BACKGROUND: Seven loci for autosomal dominant hereditary spastic paraplegia (ADHSP) have been mapped. To date, two families of SPG12 (chromosome 19q13) have been analyzed; however, there is not enough clinical information on SPG12 to establish locus-phenotype correlations. METHODS: The authors studied 60 individuals from a large Italian family with ADHSP, in which 16 members in four generations were affected. They performed genetic linkage analysis with DNA markers from currently known ADHSP loci. After database searching, one candidate gene for SPG12 was analyzed by sequencing. RESULTS: The patients in this family showed an early onset and rapid progression of symptoms, resulting in severe disability, with a large proportion of affected members requiring use of a wheelchair. By age 16, most patients had sensory disturbance. Evidence for linkage to the SPG12 locus was obtained. Obligate recombination events observed in this family have narrowed the SPG12 locus from the 16.1 cM to 11.3 cM region between markers D19S416 and D19S412. In combination with previous genetic studies, the SPG12 locus was further narrowed to the 3.3 cM region between D19S416 and D19S220. A homologue of the AAA (ATPases associated with a variety of cellular activities) protein family, proteasome 26S subunit ATPase mapped near D19S220, was excluded by sequencing. CONCLUSIONS: This study refined the SPG12 region between D19S416 and D19S220 and revealed several clinical characteristics-early onset, rapid progression, and involvement of sensory disturbance-that may be unique to SPG12. Suggestive evidence of genetic anticipation was obtained, but should be confirmed in other SPG12 families.

Association between presenilin-1 Glu318Gly mutation and familial Alzheimer's disease in the Australian population.

Mutations in the presenilin-1 (PS-1) gene on chromosome 14 account for the majority of early-onset familial Alzheimer's disease (FAD) cases. To date, more than 90 mutations have been identified and, while most of these mutations are completely penetrant, the Glu318Gly mutation has been suggested to be partially penetrant. These findings indicate that it may play a similar role to apolipoprotein E (APOE)-epsilon4 by acting as a genetic risk factor for AD. In the current study, a total of 682 subjects were tested to assess the frequency of the Glu318Gly mutation in AD in the Australian population. The Glu318Gly mutation was identified in six sporadic late-onset AD patients, four FAD patients (unrelated) and in nine control subjects. The frequency of this mutation was highest in the familial AD group (8.7%) and lowest in control subjects (2.2%). When the mutation frequencies were compared, we found a statistically significant difference between the latter two groups (Fisher's exact test, P < 0.05). The genotype frequency of the Glu318Gly mutation in all AD cases and controls in the Australian population was 2.8%. This frequency is comparable to that observed for the Dutch population (3.2%), but not for the Finnish population (6.8% and 6.0%) or the Spanish population (5.3%). These findings show that the frequency of the Glu318Gly mutation is increased in FAD patients, suggesting a potential role as a genetic risk factor contributing to the pathogenesis of familial AD.

Nicastrin binds to membrane-tethered Notch.

The presenilins and nicastrin, a type 1 transmembrane glycoprotein, form high molecular weight complexes that are involved in cleaving the beta-amyloid precursor protein (betaAPP) and Notch in their transmembrane domains. The former process (termed gamma-secretase cleavage) generates amyloid beta-peptide (Abeta), which is involved in the pathogenesis of Alzheimer's disease. The latter process (termed S3-site cleavage) generates Notch intracellular domain (NICD), which is involved in intercellular signalling. Nicastrin binds both full-length betaAPP and the substrates of gamma-secretase (C99- and C83-betaAPP fragments), and modulates the activity of gamma-secretase. Although absence of the Caenorhabditis elegans nicastrin homologue (aph-2) is known to cause an embryonic-lethal glp-1 phenotype, the role of nicastrin in this process has not been explored. Here we report that nicastrin binds to membrane-tethered forms of Notch (substrates for S3-site cleavage of Notch), and that, although mutations in the conserved 312-369 domain of nicastrin strongly modulate gamma-secretase, they only weakly modulate the S3-site cleavage of Notch. Thus, nicastrin has a similar role in processing Notch and betaAPP, but the 312-369 domain may have differential effects on these activities. In addition, we report that the Notch and betaAPP pathways do not significantly compete with each other.

Presenilin function: connections to Alzheimer's disease and signal transduction.

Missense mutations in presenilin 1 (PS1) and presenilin 2 (PS2) are associated with early-onset familial Alzheimer's disease which displays an accelerated deposition of amyloid plaques and neurofibrillary tangles. Presenilins are multi-spanning transmembrane proteins which localize primarily to the endoplasmic reticulum and the Golgi compartments. We have previously demonstrated that PS1 exists as a high-molecular-mass complex that is likely to contain several functional ligands. Potential binding proteins were screened by the yeast two-hybrid system using the cytoplasmically orientated PS1 loop domain which was shown to interact strongly with members of the armadillo family of proteins, including beta-catenin, p0071 and a novel neuron-specific plakophilin-related armadillo protein (NPRAP). Armadillo proteins can have dual functions that encompass the stabilization of cellular junctions/synapses and the mediation of signal transduction pathways. Our observations suggest that PS1 may contribute to both aspects of armadillo-related pathways involving neurite outgrowth and nuclear translocation of beta-catenin upon activation of the wingless (Wnt) pathway. Alzheimer's disease (AD)-related presenilin mutations exhibit a dominant gain of aberrant function resulting in the prevention of beta-catenin translocation following Wnt signalling. These findings indicate a functional role for PS1 in signalling and suggest that mistrafficking of selected presenilin ligands may be a potential mechanism in the genesis of AD.

Distinguishable effects of presenilin-1 and APP717 mutations on amyloid plaque deposition.

Both APP and PS-1 are causal genes for early-onset familial Alzheimer's disease (AD) and their mutation effects on cerebral Abeta deposition in the senile plaques were examined in human brains of 29 familial AD (23 PS-1, 6 APP) cases and 14 sporadic AD cases in terms of Abeta40 and Abeta42. Abeta isoform data were evaluated using repeated measures analysis of variance which adjusted for within-subject measurement variation and confounding effects of individual APP and PS-1 mutations, age at onset, duration of illness and APOE genotype. We observed that mutations in both APP and PS-1 were associated with a significant increase of Abeta42 in plaques as been documented previously. In comparison to sporadic AD cases, both APP717 and PS-1 mutation cases had an increased density (measured as the number of plaques/mm(2)) and area (%) of Abeta42 plaques. However, we found an unexpected differential effect of PS-1 but not APP717 mutation cases. At least some of PS-1 but not APP717 mutation cases had the significant increase of density and area of Abeta40-plaques as compared to sporadic AD independently of APOE genotype. Our results suggest that PS-1 mutations affect cerebral accumulation of Abeta burden in a different fashion from APP717 mutations in their familial AD brains.

Frontotemporal dementia with novel tau pathology and a Glu342Val tau mutation.

It is unclear how tau gene mutations cause frontotemporal dementia (FTD) with parkinsonism linked to chromosome 17 (FTDP-17), but those in exon 10 (E10) or the following intron may be pathogenic by altering E10 splicing, perturbing the normal 1:1 ratio of four versus three microtubule-binding repeat tau (4R:3R tau ratio) and forming tau inclusions. We report on a 55-year old woman with frontotemporal dementia and a family history of FTDP-17 in whom we found a novel E12 (Glu342Val) tau gene mutation, prominent frontotemporal neuron loss, intracytoplasmic tau aggregates, paired helical tau filaments, increased 4R tau messenger RNA, increased 4R tau without E2 or E3 inserts, decreased 4R tau with these inserts, and a 4R:3R tau ratio greater than 1 in gray and white matter. Thus, this novel Glu342Val mutation may cause FTDP-17 by unprecedented mechanisms that alter splicing of E2, E3, and E10 to preferentially increase 4R tau without amino terminal inserts and promote aggregation of tau filaments into cytopathic inclusions.

Molecular genetics of Alzheimer's disease: the role of beta-amyloid and the presenilins.

Alzheimer's disease is the most common neurodegenerative disorder of aging, accounting for an estimated two-thirds of all cases of senile dementia. Epidemiologic studies have failed to resolve any single cause of Alzheimer's disease and suggest a complex etiology, with environmental and genetic factors influencing the pathogenesis. Although the majority of cases are sporadic, a small number display familial clustering. Genetic analyses of these pedigrees have identified four genes that are involved in the development of Alzheimer's disease.

Lack of SOD1 gene mutations and activity alterations in two Italian families with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive fatal disorder, which results from the degeneration of motor neurons in the brain and spinal cord. Approximately 20% of the inherited autosomal dominant cases are due to mutations within the gene coding for Cu/Zn superoxide dismutase 1 (SOD1), a cytosolic homodimeric enzyme that catalyzes the dismutation of toxic superoxide anion. We investigated the presence of SOD1 gene mutations and activity alterations in two unrelated families of ALS patients from Elba, an island of central Italy. No mutation in SOD1 exon 1 to 5 and no activity alteration were observed in all members of the two analyzed ALS families (FALS). These data show an apparent heterogeneous distribution of ALS patients with SOD1 gene mutations among different populations and suggest that another genetic locus could be involved in the disease.

Inhibiting amyloid precursor protein C-terminal cleavage promotes an interaction with presenilin 1.

Presenilin 1 (PS1) plays a pivotal role in the production of the amyloid-beta protein, which is central to the pathogenesis of Alzheimer's disease. It has been demonstrated that PS1 regulates the gamma-secretase proteolysis of the amyloid precursor protein (APP) C-terminal fragment (APP-C100), which is the final step in amyloid-beta protein production. The mechanism and detailed pathway of this PS1 activity has yet to be fully resolved, but it may be due to a presenilin-controlled trafficking of the APP fragment or possibly an inherent PS1 proteolytic activity. We have investigated the possibility of a direct interaction of PS1 and the APP-C100 within the high molecular mass presenilin complex. However, the APP-C100 is rapidly degraded, and if it forms, then any PS1.APP complex is likely to be very transitory. To circumvent this problem, we have utilized the protease inhibitor N-acetyl-leucyl-norleucinal (LLnL) and the lysosomotropic agent NH(4)Cl, which inhibits the turnover of the APP-C100. Under these conditions, levels of the fragment increased appreciably, and as shown by glycerol gradient analysis, the APP-C100 shifted to a higher molecular mass complex that overlapped with PS1. Immunoprecipitation studies demonstrated that a significant population of the APP-C100 co-precipitated with PS1. These findings suggest that PS1 may mediate the shuttling of APP fragments and/or facilitate their presentation for gamma-secretase cleavage through a direct interaction.

Absence of linkage between familial amyotrophic lateral sclerosis and copper chaperone for the superoxide dismutase gene locus in two Italian pedigrees.

We investigated the segregation of the copper chaperone for the superoxide dismutase (CCS) gene in two Italian families with amyotrophic lateral sclerosis lacking the mutations in superoxide dismutase 1 gene. We analyzed a total of 56 individuals; six people were affected. Diagnoses were made using the El Escorial criteria. The results of our study provide no evidence of a linkage between markers flanking the CCS gene and familial amyotrophic lateral sclerosis (FALS) in these FALS kindreds.

Association between angiotensin-converting enzyme and Alzheimer disease.

BACKGROUND: Angiotensin-converting enzyme has been reported to show altered activity in patients with neurologic diseases. An insertion-deletion polymorphism in ACE has recently been linked to heart disease, cerebrovascular disease, and AD. OBJECTIVE: To determine whether the angiotensin-converting enzyme (ACE) is associated with risk of Alzheimer disease (AD). METHODS: We investigated the ACE polymorphism as a potential risk factor for AD in 151 patients with AD and 206 ethnically matched controls from Russia and in 236 patients with AD and 169 controls from North America by means of allele association methods and logistic regression. RESULTS: None of the ACE genotypes was associated with increased susceptibility to AD in the total sample or in subsets stratified by apolipoprotein E gene (APOE) epsilon4 status. However, the D allele was more frequent among AD cases between ages 66 and 70 years compared with controls in both the Russian (P = .02) and North American (P = .001) datasets. In this age group, the effect of D (odds ratio, 11.2; 95% confidence interval, 2.9-44.0) appeared to be independent of and equal or greater in magnitude to the effect of APOE epsilon4 (odds ratio, 7.8; 95% confidence interval, 3.5-7.4). CONCLUSIONS: Our results suggest that APOE and ACE genotypes may be independent risk factors for late-onset AD, but the ACE association needs to be confirmed in independent samples in which the time and extent of vascular cofactors can be assessed.

Molecular genetics of Alzheimer's disease.

Application of genetic paradigms to Alzheimer's disease (AD) has led to confirmation that genetic factors play a role in this disease. Additionally, researchers now understand that AD is genetically heterogeneous and that some genetic isoforms appear to have similar or related biochemical consequences. Genetic epidemiologic studies indicate that first-degree relatives of AD probands have an age-dependent risk for AD approximately equal to 38% by age 90 years (range 10% to 50%). This incidence strongly suggests that transmission may be more complicated than a simple autosomal dominant trait. Nevertheless, a small proportion of AD cases with unequivocal autosomal dominant transmission have been identified. Studies of these autosomal dominant familial AD (FAD) pedigrees have thus far identified four distinct FAD genes. The beta-amyloid precursor protein (beta APP) gene (on chromosome 21), the presenilin 1 (PS1) gene (on chromosome 14), and the presenilin 2 (PS2) gene (on chromosome 1) gene are all associated with early-onset AD. Missense mutations in these genes cause abnormal beta APP processing with resultant overproduction of A beta 42 peptides. In addition, the epsilon 4 allele of apolipoprotein E (APOE) is associated with a increased risk for late-onset AD. Although attempts to develop symptomatic treatments based on neurotransmitter replacement continue, some laboratories are attempting to design treatments that will modulate production or disposition of A beta peptides.

Genetic factors in the genesis of Alzheimer's disease.

At least four different genes have been identified that are associated with inherited susceptibiltiy to Alzheimer's disease. Some of the genes are highly penetrant (PS1, PS2, beta APP); the other, APOE, is a weaker susceptibility factor. Several additional genes are suspected to exist but have not yet been cloned.