Familial Alzheimer's disease: genetic influences on the disease process (Review).

Alzheimer's disease (AD) has both genetic and environmental etiologies. Genetic causes include presenilin (PS) mutations on chromosomes 1 and 14, and amyloid precursor protein (APP) mutations on chromosome 21. At least two susceptibility genes also exist. In this review phenotypic differences in AD groups are described and possible differences in the mechanism(s) by which AD mutations lead to dementia are reviewed. Clinical, pathological and biochemical phenotypes distinguish AD cases with different etiologies. For example, age-at-onset and age-at-death between PS-1, PS-2, APP and sporadic AD groups differ. Also, some forms of AD are associated with more Abeta deposition others, and some AD groups have morphologically distinct Abeta deposits or other unique histopathologic features. APP-related AD mutations always occur within the Abeta portion of the APP gene, adjacent to sites where alpha-, beta- and gamma-secretase breakdown pathways operate in the expressed protein. These mutations alter APP metabolism leading to increased Abeta production. It is unknown if other AD groups are subject to identical changes in APP metabolism. Activation of apoptosis pathways, more general defects in protein transport or metabolism, differential regulation of tau kinases or other factors may also be important. Overall, data support the notion that differences occur in the disease process in etiologically distinct AD groups.     

阿尔茨海默病及其药物治疗进展

阿尔茨海默病(Alzheimer′s disease,AD)是一种较为严重的中枢神经系统退行性病变,其机制尚未明了,尚无有效根治药物,目前已成为一种社会广为关注的慢性疾病。本文从预防治疗、症状性治疗、疾病调节治疗和中医药治疗四个方面来阐述AD的药物治疗情况。     

Familial Alzheimer's disease presenilin-1 mutants potentiate cell cycle arrest

We previously reported that overexpression of presenilin 1 and 2 (PS1 and PS2) in HeLa cells leads to cell cycle arrest, and that the PS2(N141I) FAD mutant potentiates cell cycle arrest compared to wild-type PS2. Using similar BrdU incorporation studies we now report that three different PS1 FAD mutants also increase cell cycle arrest compared to wild-type PS1when overexpressed in either HeLa cells or an ATM deficient cell line. We detected reproducible differences in the degrees to which these FAD mutants induced arrest. PS1(P117L) reduced BrdU incorporation the most (13 to 14%) followed by PS1(P267S) (7.5 to 9%), with the PS1(E280A) mutant inhibiting BrdU incorporation the least (6 to 7%), compared to wild-type PS1. The degree to which the different mutants inhibited cell cycle progression correlates somewhat with the age of AD onset induced by the mutations in carriers. Immunoblot analysis of protein extracts from presenilin-overexpressing cells indicates that the cell cycle-regulated cytoplasmic pool of β-catenin is dramatically reduced, whereas the insoluble β-catenin pool remains essentially unaffected. We discuss the implications of these findings in relationship to cell cycle arrest, apoptosis and AD.     

Familial Alzheimer's disease: genetic analysis related to disease heterogeneity, Down syndrome and human brain evolution

Etiologically heterogeneous subgroups of patients with Alzheimer's disease (AD) exist and need to be distinguished so as to better identify genetic causes of familial cases. Furthermore, the presence of AD neuropathology in Down syndrome (trisomy 21) subjects older than 35 years suggests that AD in some cases is caused by dysregulation of expression of genes on chromosome 21. Cerebral metabolic abnormalities in life, and the distribution of AD neuropathology in the post-mortem brain, indicate that AD involves the association neocortices and subcortical regions with which they evolved during evolution of the human brain. Accordingly, understanding the molecular basis of this evolution should elucidate the genetic basis of AD, whereas knowing the genetics of AD should be informative about the genomic changes which promoted brain evolution.     

Epigenetic mechanisms in Alzheimer's disease: progress but much to do

The interesting review from Mastroeni and colleagues highlights recent progress on epigenetic analysis of Alzheimer's disease, but it also illustrates how much we still need to do.     

阿尔茨海默病老年斑相关研究进展

正阿尔茨海默病(Alzheimer's disease,AD)是一种以进行性痴呆为特征的年龄相关性神经退行性疾病,老年斑(senile plaques,SP)为其典型病理特征之一~([1-2])。随着世界范围内老龄化社会的到来,AD发病率呈逐年递增趋势。来自世界卫生组织的报道称,目前全世界范围内该病患者高达3 560万,每20年患病人数将翻一番,预计2050年可达到1.154亿人~([3]),这一疾病正在成为国际神经疾病研究的热点。1907年,德国神经病理学     

Familial Alzheimer's mutation: mRNA secondary structure revisited.

It has been suggested that the mutation at position 717 of the amyloid precursor protein (APP), found in several cases of familial Alzheimer's disease, affects the secondary structure of the corresponding messenger RNA and the rate of its translation (10). Phylogenetic analysis based on comparison with other mammalian APP sequences does not support this possibility.     

Characterizing sleep problems in persons with Alzheimer's disease and normal elderly

We retrospectively analyzed sleep disturbance symptoms and estimated time in bed from the intake interviews of 399 healthy, non-demented elderly (NDE) and 263 persons with a diagnosis of possible (n = 53) or probable (n = 210) Alzheimer's disease (AD). Our primary objective was to identify what symptoms might underlie an individual's perception of 'sleep problems' and to determine if these were consistent within, and across, our two cohorts. We stratified each cohort according to whether or not they (or their caregiver) indicated that they had a 'sleep problem', and compared the frequency and endorsement rates of each of 21 sleep disturbance symptoms across those who did or did not endorse 'sleep problem'. For less than half of the symptoms in persons with AD, and a quarter of those in NDE, endorsement rates were significantly different depending on whether the reporter (or their sleep partner) did or did not report a sleep problem. Differences in mean frequency ratings between individuals reporting sleep problems relative to those not reporting were observed on 10 symptoms in both cohorts; six of these were the same symptom for both cohorts. When persons with subjective sleep problems in the AD and NDE cohorts were compared, only four of 21 symptoms were endorsed in one and not the other; two symptoms were significantly more frequent in one cohort than the other. Thus, within cohorts, the differences between persons with and without 'sleep problems' were relatively pronounced while the main differences in specific sleep-related symptoms between AD and NDE were not. Observed between-cohort differences appear to be driven by who is reporting, and the high prevalence of daytime sleeping in AD. Within-cohort differences reflect a clear distinction between persons with and without sleep problems, regardless of the reporter.     

Familial Alzheimer's disease co-segregates with a Met 146 Ile substitution in presenilin-1

The presenilin-1 ( PS-1 )/ S 182 gene at chromosome 14q24.3 is, when mutated, the most common disease gene in autosomal dominant early-onset Alzheimer's disease. Substitution of methionine 146 of the gene product for either valine or leucine co-segregates with Alzheimer's disease with the age of onset in the late thirties or early forties. Here we describe a new substitution of methionine 146 for isoleucine that co-segregates with Alzheimer's disease with age of the onset in the early forties. All identified missense mutations in methionine codon 146 replace one hydrophobic amino acid (Met) with another (Val, Leu, Ile) and correspond to any nucleotide change at the first or third position of the codon. Second position mutations invariably lead to replacement of the hydrophobic methionine with a hydrophilic amino acid that may severely affect the function of the protein. The fact that no second position mutations have been identified so far may support the hypothesis that the protein product of PS-1 plays a crucial role during development.     

Prion disease and Alzheimer's disease: pathogenic overlap

Prion diseases are widely recognized for their transmissibility, and it is this feature that has been studied most extensively. In recent years, public health concerns over the transmission of animal forms of prion disease, such as bovine spongiform encephalopathy and chronic wasting disease, to humans has only augmented the notion that prion diseases are primarily infectious. Yet within the spectrum of human prion diseases, often overlooked is the fact that the overwhelming majority of cases are age-dependent sporadic, or inherited processes. Closer examination of the pathophysiological processes involved in prion disease further indicates a neurodegenerative, rather than infectious disease. Indeed, the age requirement, the numerous kindreds carrying point mutations in an amyloidogenic protein, the copper binding properties of the amyloidogenic protein, the evidence of free radical damage, the presence of polymorphisms that influence disease susceptibility, the formation of amyloid plaques, and in some cases the presence of neurofibrillary pathology, are features common to both prion disease and Alzheimer's disease. Therefore, while transmissibility will continue to be a major subject of prion disease research, we suspect that further characterization of its pathophysiological mechanisms will only substantiate the notion that prion disease is fundamentally a neurodegenerative process.     

TB vaccines: progress and problems

Tuberculosis (TB) is the biggest killer worldwide of any infectious disease, a situation worsened by the advent of the HIV epidemic and the emergence of multi-drug resistant strains of Mycobacterium tuberculosis. The existing vaccine, Mycobacterium bovis bacille Calmette-Guérin (BCG), has proven inefficient in several recent field trials. There is currently intense research using cutting-edge vaccine technology to combat this ancient disease. However, it is necessary to understand why BCG has failed before we can rationally develop the next generation of vaccines. Several hypotheses that might explain the failure of BCG and the strategies designed to address these shortcomings are discussed.     

Alzheimer's disease and Alzheimer's dementia: distinct but overlapping entities

Much of the controversy about the “amyloid cascade hypothesis” may reflect unrecognized differences in the use of language, including the use of the word “cause.” This commentary proposes that the term Alzheimer disease refer to the neuropathological entity and the term Alzheimer dementia to clinical dementia in people who also have Alzheimer neuropathology. The ultimate causes of Alzheimer disease are proposed to be aging, environmental stresses, and genetic predispositions. The fundamental cause of Alzheimer dementia is proposed to be Alzheimer disease, i.e. the neurobiological abnormalities in Alzheimer brain. The neurobiology of Alzheimer disease includes changes that may initially be adaptive but can become excessive and thereby harmful; they include increased expression of APP with accumulation of potentially damaging peptides such as Aβ, inflammation, and increased ROS activity. The neurobiological abnormality that is the proximate cause of Alzheimer dementia appears to be decreases in cerebral metabolic rate. Decreased metabolism occurs not only in this but in essentially all dementias, and impairing brain metabolism induces neuropsychological deficits characteristic of dementias. The immediate cause of Alzheimer dementia is proposed to be deficiencies in signaling, both intracellular and intercellular (neurotransmission), that follow directly from the decrease in cerebrometabolic rate.     

神经细胞粘附分子与老年性痴呆突触可塑性研究进展

目的:神经细胞粘附分子(NCAM)是细胞粘附分子中的一种,它介导细胞间的粘附,既有许多有益的生物学作用,又与许多疾病的发生发展有关。近来研究表明,NCAM与老年性痴呆的神经元突触可塑性关系密切,参与了其学习记忆过程。本文将概述NCAM的结构和功能及其与老年性痴呆突触可塑性的研究进展。     

Familial cushing disease

A 28-year-old woman and her niece presented with manifestations of the Cushing syndrome. Endocrine studies, including small- and large-dose dexamethasone-suppression tests confirmed the diagnosis of pituitary ACTH excess. The first patient had a sella of normal size and went into clinical and hormonal remission after external pituitary irradiation, and she has remained well on follow-up for 9 years. The niece had an enlarged sella turcica on tomography and is receiving a course of external pituitary irradiation.     

Mucosal viral vaccines: progress and problems

Data obtained in the recent years on developing the viral inactivated mucosal vaccines by applying the mucosal-adhesive adjuvants are presented in the survey. Progress achieved in designing the mucosal influenza vaccines and mucosal vaccines against a variety of other viral infections is pointed out. Cross-protection against variations of a virus within its subtype limits as well as overcoming of a negative influence of parent antibodies produced on the immunogenicity of live-vaccines', which were used at young age, were observed in the intranasal administration of viral mucosal vaccines. A number of shortcomings of bacterial toxins used as mucosal-adhesive adjuvants as well as problems, which may arise when the viral mucosal vaccines are used on a large-scale basis due to a need in their two- and-threefold intranasal administration, are in the focus of attention.     

Hepatitis C: progress and problems.

The hepatitis C virus (HCV), a single-stranded RNA virus, is the major cause of posttransfusion hepatitis. HCV isolates differ in nucleotide and amino acid sequences. Nucleotide changes are concentrated in hypervariable regions and may be related to immune selection. In most immunocompetent persons, HCV infection is diagnosed serologically, using antigens from conserved regions. Amplification of RNA may be necessary to detect infection in immunosuppressed patients. Transmission by known parenteral routes is frequent; other means of spread are less common and may represent inapparent, percutaneous dissemination. Infection can lead to classical acute hepatitis, but most infected persons have no history of acute disease. Once infected, most individuals apparently remain carriers of the virus, with varying degrees of hepatocyte damage and fibrosis ensuing. Chronic hepatitis may lead to cirrhosis and hepatocellular carcinoma. However, disease progression varies widely, from less than 2 years to cirrhosis in some patients to more than 30 years with only chronic hepatitis in others. Determinants important in deciding outcome are unknown. Alpha interferon, which results in sustained remission in selected patients, is the only available therapy. Long-term benefits from such therapy have not been demonstrated. Prevention of HCV infection by vaccination is likely to be challenging if ongoing viral mutation results in escape from neutralization and clearance.