LR11/SorLA expression is reduced in sporadic Alzheimer disease but not in familial Alzheimer disease

LR11 is an ApoE receptor that is enriched in the brain. We have shown that LR11 is markedly downregulated in patients with sporadic Alzheimer disease (AD). This finding led us to explore whether reduced LR11 expression reflects a primary mechanism of disease or merely a secondary consequence of other AD-associated changes. Therefore, LR11 expression was assessed in a transgenic mouse model of AD and familial AD (FAD) brains. Immunohistochemistry and immunoblotting of LR11 in PS1/APP transgenic and wild-type mice indicated that LR11 levels are not affected by genotype or accumulation of amyloid pathology. LR11 expression was also evaluated based on immunoblotting and LR11 immunostaining intensity in human frontal cortex in controls, sporadic AD, and FAD, including cases with presenilin-1 (PS1) and presenilin-2 (PS2) mutations. Although LR11 was reduced in sporadic AD, there was no difference in protein level or staining intensity between control and FAD cases. The finding that LR11 expression is unaffected in both a mouse model of AD and autosomal-dominant forms of AD suggests that LR11 is not regulated by amyloid accumulation or other AD neuropathologic changes. We hypothesize that LR11 loss may be specific to sporadic AD and influence amyloid pathology through mechanisms independent of substrate-enzyme interactions regulated by FAD mutations.     

AMY plaques in familial AD: comparison with sporadic Alzheimer's disease

OBJECTIVE: To assess AMY expression in familial AD (FAD). BACKGROUND: The discovery of nonbeta-amyloid (Abeta), plaque-like deposits composed of a 100-kd protein (AMY) in sporadic AD (SAD) brains prompted us to determine whether these plaques (AMY plaques) also occur in AD due to mutations of the presenilin-1 (PS-1), presenilin-2 (PS-2), or the amyloid precursor protein (APP) genes. METHODS: We used immunohistochemistry and confocal laser scanning microscopy to probe the brains of 22 patients with FAD (13 with PS-1, 5 with PS-2, and 4 with APP mutations) and 14 patients with SAD. RESULTS: AMY plaques were present in all SAD and FAD brains, including an FAD/PS-1 brain from an individual with preclinical disease. The morphology of AMY plaques in SAD and FAD brains was indistinguishable, but they differed from Abeta deposits because AMY plaques lacked an immunoreactive core. AMY plaques sometimes colocalized with Abeta(x-42) deposits, but they did not colocalize with Abeta(x-40) plaque cores in either SAD or FAD brains. The percent of cortical area occupied by AMY was greater in FAD than in SAD brains (mean percent area = 9.8% and 5.9%, t = 2.487, p = 0.018). In particular, APP and PS-1 cases had more AMY deposition than PS-2 or SAD cases (12.9%, 10.5%, 6.2% in APP, PS-1, and PS-2 AD). CONCLUSIONS: AMY plaques are consistently present in familial AD due to presenilin-1 (PS-1), PS-2, and amyloid precursor protein mutations, and they can begin to accumulate before the emergence of dementia.     

Early-onset familial Alzheimer's disease (EOFAD)

Early-onset familial Alzheimer's disease (EOFAD) is a condition characterized by early onset dementia (age at onset < 65 years) and a positive family history for dementia. To date, 230 mutations in presenilin (PS1, PS2) and amyloid precursor protein (APP) genes have been identified in EOFAD. The mutations within these three genes (PS1/PS2/APP) affect a common pathogenic pathway in APP synthesis and proteolysis, which lead to excessive production of amyloid β. Compared with sporadic Alzheimer's disease (AD), EOFAD has some distinctive features including early age at onset, positive familial history, a variety of non-cognitive neurological symptoms and signs, and a more aggressive course. There is marked phenotypic heterogeneity among different mutations of EOFAD. Studies in presymptomatic mutation carriers reveal biomarkers abnormalities. EOFAD diagnosis is based on clinical and family history, neurological symptoms and examination, biomarker features, as well as genotyping in some cases. New therapeutic agents targeting amyloid formation may benefit EOFAD individuals.     

Genetic counseling and testing for families with Alzheimer's disease

With the identification of the genes responsible for autosomal dominant early-onset familial Alzheimer's disease (FAD genes), there is a considerable interest in the application of this genetic information in medical practice through genetic testing and counseling. Pathogenic mutations in the PSEN1 and PSEN2 genes encoding presenilin-1 and -2, and the APP gene encoding amyloid b precursor protein, account for 18-50% of familial EOAD cases with autosomal dominant pattern of inheritance. A clinical algorithm of genetic testing and counseling proposed for families with AD has been presented here. A screening for mutations in the APP, PSEN1, and PSEN2 genes is available to individuals with AD symptoms and at-risk children or siblings of patients with early-onset disease determined by a known mutation. In an early-onset family, a known mutation in an affected patient puts the siblings and children at a 50% risk of inheriting the same mutation. The goal of genetic testing is to identify at-risk individuals in order to facilitate early and effective treatments in the symptomatic person based on an individual's genotype and strategies to delay the onset of disease in the presymptomatic mutation carriers. However, there are several arguments against the use of genetic testing both presymptomatically (unpredictable psychological consequences of information about a genetic defect for family members) and as a diagnostic tool for the differential diagnosis of dementia in general practice (a risk of errors in an interpretation of mutation penetrance and its secondary effects on family members, especially for novel mutations; the possibility of coexistence of another form of dementia at the presence of a mutation). Currently, APOE genotyping for presymptomatic individuals with a family history of late-onset disease is not recommended. The APOE4 allele may only confer greater risk for disease, but its presence is not conclusive for the development of AD.     

Identification of a Novel Mutation in the Presenilin 1 Gene in a Chinese Alzheimer’s Disease Family

This study has identified a gene mutation in a Chinese family with Alzheimer’s disease (AD). Family members were screened by a set of medical examinations and neuropsychological tests. Their DNA was extracted from blood cells and sequenced for gene mutation in the amyloid precursor protein (APP), the presenilin 1 (PS1) and the presenilin 2 (PS2) genes. Genetic analysis showed that the AD patients in the family harbored a T to G missense mutation at the position 314 in exon 4 of the PS1 gene, resulting in a change of F105C in amino acid sequence. Clinical manifestation of these patients included memory loss, counting difficulty, personality change, disorientation, dyscalculia, agnosia, aphasia, and apraxia, which was similar to that of the familial AD (FAD) patients harboring other PS1 mutations. We intend to add a novel mutation F105C of the PS1 gene to the pool of FAD mutations. With the current available genetic data, mutations of the PS1 gene account for the majority of gene mutations in Chinese FAD.     

Early-onset Alzheimer disease caused by a new mutation (V717L) in the amyloid precursor protein gene

CONTEXT: Alzheimer disease is the most common form of dementia. Mutations in the genes amyloid precursor protein (APP), presenilin 1(PS1) and presenilin 2(PS2) have been found in early-onset familial forms of Alzheimer disease OBJECTIVE: To determine the cause of dementia in a family with early-onset illness. DESIGN, SETTING, AND PARTICIPANTS: A family with a history of dementia was referred to the Indiana Alzheimer Disease Center, Indianapolis. All the research in this study was done in a university or university hospital. The proband and her 4 siblings took part in the study. The proband, who is still alive, showed symptoms of Alzheimer disease at 38 years of age. Genomic DNA was obtained from blood samples of 5 family members. The APPandPS1genes of the proband were screened for mutations by amplification followed by direct sequencing. RESULTS: Sequence of exon 17 of the APPgene revealed a single nucleotide (guanine to cytosine) substitution in 1 allele, resulting in an amino acid change at codon 717 (valine to leucine). Each of the proband's siblings were tested for this mutation by direct sequencing. Two of the 4 were found to have the mutation; one of whom was recently clinically diagnosed at the age of 36 years. CONCLUSIONS: A novel mutation in the APPgene (V717L) has been found in a family with a history of dementia, beginning in the mid to late 30s. The age of onset in this family is earlier than most of the other families with Alzheimer disease who also have APPmutations. Arch Neurol. 2000.     

Identification of new presenilin gene mutations in early-onset familial Alzheimer disease

BACKGROUND: Mutations in the presenilin 1 (PS1) and presenilin 2 (PS2) genes, and more rarely in beta-amyloid precursor protein (betaAPP), underlie the pathogenesis of most cases of familial Alzheimer disease (FAD). OBJECTIVE: To screen the entire coding region of the PS1 and PS2 genes and exons 16 and 17 of the betaAPP to find pathogenetic mutations in FAD.Patients Patients with FAD were consecutively enrolled from among the outpatients from the neurology departments at the Universities of Florence and Parma and the Santa Maria Nuova Hospital in Reggio Emilia, Italy. DESIGN AND METHODS: Polymerase chain reaction-single-strand conformation polymorphism and DNA se-quencing were used to investigate the affected members of families with FAD. RESULTS: We identified a family carrying a novel Ser130Leu mutation in the PS2 gene. Moreover, we found 2 novel PS1 mutations: Cys92Ser in exon 4 in 2 unrelated families and Leu174Met in exon 6 in the PS1 gene. We also found a fourth Italian family with the betaAPP Val717Ile mutation. CONCLUSIONS: One novel PS2 mutation associated with highly penetrant but variable age at onset (35-85 years) and 2 novel PS1 missense mutations associated with early-onset Alzheimer disease at age 49 to 54 years have been identified in Italian families. Screening for new mutations in presenilin and betaAPP genes was beneficial in characterizing gene function in FAD.     

A novel presenilin-1 mutation (Leu85Pro) in early-onset Alzheimer disease with spastic paraparesis

BACKGROUND: Early-onset familial Alzheimer disease is caused by mutations in the amyloid precursor protein (APP), presenilin-1 (PSEN1), or presenilin-2 (PSEN2) genes. Phenotypic diversity has been reported to be associated with various mutations in PSEN1. Various mutations of PSEN1 have been reported in cases of early-onset Alzheimer disease with spastic paraparesis. OBJECTIVE: To describe a novel mutation in the PSEN1 gene associated with early-onset Alzheimer disease with spastic paraparesis. PATIENT AND METHODS: The patient was a 27-year-old man who developed early-onset dementia with spastic paraparesis. We examined sequences of the PSEN1, PSEN2, and APP genes from the patient and his family. To detect a possible mutation effect on the production of amyloid-beta peptide (Abeta), transfected HEK293 cells were examined for Abeta42 and Abeta40 production. RESULTS: We found a novel mutation (Leu85Pro) in PSEN1. This mutation influenced the production of Abeta, resulting in a 2-fold elevation of Abeta42 production and of the Abeta42/40 ratio. CONCLUSION: To our knowledge, this is the first report of very early-onset Alzheimer disease with spastic paraparesis and with the visual variant form of the disease, which is associated with visuospatial cognitive disorder. The Leu85Pro mutation in PSEN1 was pathogenic.     

Novel mutations and repeated findings of mutations in familial Alzheimer disease

Twenty-one unrelated patients with a history of suspected familial Alzheimer disease (FAD) were screened for mutations in PSEN1, PSEN2, and APP, the known FAD genes encoding the presenilins (PS1 and PS2) and the amyloid precursor protein (APP). The mutation detection rate was 57%. Of the nine pathogenic mutations found in 12 cases, three were in APP, one in PSEN2, and five in PSEN1, including two novel Greek mutations (L113Q and N135S). Whereas our findings suggest the possibility of single founders for the majority of mutations, we found evidence of recurrence of the APP mutations V717L and V717I.     

Amyloid precursor protein gene analysis in familial Alzheimer's disease cases: a lack of mutations in exons 16 and 17

The beta-amyloid precursor protein (APP) gene (on chromosome 21), Presenilin 1 (PS1) gene (on chromosome 14) and Presenilin 2 (PS2) gene (on chromosome 1) are responsible for autosomal dominant early-onset Alzheimer's disease (EOAD). Missense mutations in these genes cause abnormal APP processing with subsequent overproduction of amyloidogenic and toxic A beta (42 peptide. A mutational analysis of APP, PS1, and PS2 genes can be used for both symptomatic and presymptomatic genetic testing and counselling in familial Alzheimer's disease (FAD). To contribute to our knowledge on genetic background of Alzheimer's disease in Poland, we screened APP mutations in a sample of familial EOAD cases from Poznan region. We did not find pathogenic mutations within exons 16 and 17 of the APP gene. Our study confirmed that APP gene mutations account only for a very small portion of FAD.     

Mouse models of Alzheimer's disease: the long and filamentous road

Alzheimer's disease (AD) is characterized by memory impairment leading to dementia, deposition of amyloid plaques and neurofibrillary tangles (NFTs), and neuronal loss. The major component of plaques is the amyloid beta peptide, A beta, whereas NFTs contain hyperphosphorylated forms of the microtubule-associated protein tau (tau). Familial AD (FAD) mutations either elevate A beta synthesis by favoring 'secretase' of the Alzheimer beta-amyloid precursor protein (APP) or enhance the fibrillogenic properties of this peptide. Mutations in the tau gene cause a different disease denoted FTPD-17, but suggest that the aberrant forms of tau seen in AD are unlikely to be benign. These findings imply a complex pathogenic cascade in AD and important goals of transgenic modeling are to capture and stratify this pathogenic process. Several laboratories have created APP transgenic (Tg) mice that exhibit AD-like amyloid pathology and A beta burdens. These Tg lines also exhibit deficits in spatial reference and/or working memory, with immunization against A beta attenuating both AD-associated phenotypes. Tangle-like pathologies are observed in mice expressing FTPD-17 mutant forms of tau, but florid tau pathologies based upon the wild type (wt) tau isoforms present in AD have proven more elusive. Creation of animal models with robust amyloid and tau pathologies, yet free of irrelevant confounding pathologies, remains a major objective in this field.     

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.     

Human wild presenilin-1 mimics the effect of the mutant presenilin-1 on the processing of Alzheimer's amyloid precursor protein in PC12D cells

Most familial early-onset Alzheimer's disease (FAD) is caused by mutations in the presenilin-1 (PS1) gene. Abeta 42 is derived from amyloid precursor protein (APP) and increased concentrations are widely believed to be a pathological hallmark of abnormal PS function. Thus, the interaction between PS1 and APP is central to the molecular mechanism of AD. To examine the effect of wild-type human PS1 on rat APP metabolism, we made several PC12D cell lines that expressed human wild or mutant PS1, and analyzed the processing of endogenous rat APP and the intracellular gamma-secretase activity. We found the ratio of Abeta 42/Abeta 40 increased in PC12D cells expressing wild-type human PS1. These changes were identical to those found in PC12D cells expressing human PS1 bearing the A260V mutation. These results suggest that APP metabolism is physiologically regulated by the PS1 and that loss of normal PS1 affects gamma-secretase activity.     

Familial non-Alzheimer dementia]

This is an abstract of my lecture on familial non-Alzheimer dementia. 1. Vascular dementia 1) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by autosomal dominant inheritance, smooth muscle cell degeneration and granular osmiophilic material (GOM) in arterioles, and Notch 3 mutations. 2) CARASIL This is an autosomal recessive vascular dementia with unknown etiology. 3) Familial amyloid angiopathy Familial cerebral hemorrhage and dementia is caused by mutations in amyloid precursor protein, cystatin c, and Bri genes. 2. Familial non-Alzheimer degenerative dementia 1) Dementia with Lewy bodies This is characterized by Alzheimer like dementia, visual hallucination and diffuse Lewy bodies which are formed by ubiquitinated alpha-synuclein. Occasionally, familial forms are reported, but gene mutations are unknown. 2) Frontotemporal dementia (FTD) FTDP-17 is characterized by tau mutations, character and personal changes, and disinhibition. The gene mutations were also found in familial forms of Pick's disease, corticobasal degeneration, and other tauopathies. 3) Familial British dementia (FBD), familial Danish dementia (FDD) FBD and FDD are characterized by Abri amyloid deposits, amyloid angiopathy and dementia. Mutations in Bri gene are reported. 4) Familial encephalopathy with neuroserpin inclusion bodies (FENIB) FENIB is characterized by dementia, Collins body and neuroserpin gene mutation.     

Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations

BACKGROUND: Mutations in the presenilin-1 gene (PS1) account for a majority of patients with early-onset familial AD. However, the clinical indications and algorithms for genetic testing in dementia are still evolving. METHODS: The entire open reading frame of the PS1 gene was sequenced in a series of 414 consecutive patients referred for diagnostic testing, including 372 patients with AD and 42 asymptomatic persons with a strong family history of AD. RESULTS: Forty-eight independent patients screened had a PS1 mutation including 21 novel mutations. In addition, 3% of subjects (11/413) had a known polymorphism, the Glu318Gly substitution. The majority of the mutations were missense substitutions but there were three insertions and Delta exon 10 mutation. With six exceptions (codons 35, 178, 352, 354, 358, and 365) most of the mutations occurred at residues conserved in the homologous PS2 gene or in PS1 of other species. CONCLUSIONS: Eleven percent of a referral-based series of patients with AD can be explained by coding sequence mutations in the PS1 gene. The high frequency of PS1 mutations in this study indicates that screening for PS1 mutations in AD is likely to be successful, especially when directed at patients with a positive family history with onset before 60 years (90% of those with PS1 mutations were affected by age 60 years). This will also have significance for the secondary identification of at-risk relatives who might be candidates for future prophylactic therapies for AD.     

The biological and pathological function of presenilin proteins – simple cell systems and a worm in Alzheimer’s disease research

Alzheimer’s disease (AD) is the most common form of dementia.In a small number of cases AD is genetically inherited. Mutations are associated with so far three genes. These genes encode the β-amyloid precursor protein (βAPP), as well as presenilin (PS) 1 and -2. Mutations in all three genes affect the generation of amyloid β-peptide (Aβ), which is the major component of senile plaques. Mutations in the PS genes occur much more frequently as those associated with the βAPP gene and can cause the earliest onset of AD ever recorded. PS genes are not only involved in familial AD but also play a functional role in the general production of Aβ. Therefore PS proteins are key molecules, which will allow us to understand fundamental aspects of the molecular mechanisms involved in AD. Here we will summarize the pathological as well as biological function of PS and demonstrate that simple systems, such as cultured cells and the worm Caenorhabditis elegans can be used for modern AD research.     

Rare causes of early-onset dystonia-parkinsonism with cognitive impairment: a de novo <Emphasis Type="Italic">PSEN-1</Emphasis> mutation

Mutations in PSEN1 are responsible for familial Alzheimer’s disease (FAD) inherited as autosomal dominant trait, but also de novo mutations have been rarely reported in sporadic early-onset dementia cases. Parkinsonism in FAD has been mainly described in advanced disease stages. We characterized a patient presenting with early-onset dystonia-parkinsonism later complicated by dementia and myoclonus. Brain MRI showed signs of iron accumulation in the basal ganglia mimicking neurodegeneration with brain iron accumulation (NBIA) as well as fronto-temporal atrophy. Whole exome sequencing revealed a novel PSEN1 mutation and segregation within the family demonstrated the mutation arose de novo.We suggest considering PSEN1 mutations in cases of dystonia-parkinsonism with positive DAT-Scan, later complicated by progressive cognitive decline and cortical myoclonus even without a dominant family history.     

Alzheimer's disease: a dysfunction of the amyloid precursor protein(1)

In this review, we argue that at least one insult that causes Alzheimer's disease (AD) is disruption of the normal function of the amyloid precursor protein (APP). Familial Alzheimer's disease (FAD) mutations in APP cause a disease phenotype that is identical (with the exception that they cause an earlier onset of the disease) to that of 'sporadic' AD. This suggests that there are molecular pathways common to FAD and sporadic AD. In addition, all individuals with Down syndrome, who carry an extra copy of chromosome 21 and overexpress APP several-fold in the brain, develop the pathology of AD if they live past the age of 40. These data support the primacy of APP in the disease. Although APP is the source of the beta-amyloid (Abeta) that is deposited in amyloid plaques in AD brain, the primacy of APP in AD may not lie in the production of Abeta from this molecule. We suggest instead that APP normally functions in the brain as a cell surface signaling molecule, and that a disruption of this normal function of APP is at least one cause of the neurodegeneration and consequent dementia in AD. We hypothesize in addition that disruption of the normal signaling function of APP causes cell cycle abnormalities in the neuron, and that these abnormalities constitute one mechanism of neuronal death in AD. Data supporting these hypotheses have come from investigations of the molecular consequences of neuronal expression of FAD mutants of APP or overexpression of wild type APP, as well as from identification of binding proteins for the carboxyl-terminus (C-terminus) of APP.     

beta-amyloid cascade: current status and future directions]

The deposition of amyloid beta peptides (A beta) is one of the pathological hallmarks of Alzheimer's disease (AD) brains. A beta are composed of 40-42 amino acid peptides that are proteolytically cleaved from beta APP. The deposition as diffuse plaques of a species of A beta ending at the 42nd residue (A beta 42) is one of the earliest pathological changes of AD. Importantly, mutations in beta APP genes located in positions flanking the A beta sequences have been shown to cosegregate with the clinical manifestations of AD in a subset of familial AD (FAD) pedigrees. Moreover, mutations in presenilin (PS) 1 and 2, novel polytopic membrane proteins identified as causative molecules for the majority of FAD, also increase the production of A beta 42. These results support the notion that A beta (42) plays a key role in the cascadic development of AD. Recently, PS 1 and PS 2 are shown to be the catalytic subunits of gamma-secretase that cleave the intramembrane segments of beta APP and Notch. Future therapeutic approaches to reduce amyloid deposition, including inhibitors for beta- and gamma-secretases, as well as beta-amyloid vaccine therapy, raise high hopes towards the cure and prevention of AD, although the outcome thereof would be key to the consistency of amyloid cascade hypothesis.