Hum Mol Genet 1997; 6: 1933, Nature 389, 677-678 (1997) and Michael McCarthy Oct 18, 1997 LancetAlzheimer's disease: The extracellular plaques of amyloid-beta (A-beta) peptide that form in the brains of pateints with Alzheimer's disease are thought to be involved in neurodegeneration but, until now, nobody was sure how A-beta interfered with neuronal function. The finding that A-beta interacts with the newly discovered endoplasmic-reticulum-associated binding protein (ERAB) in neurons may help to solve this puzzle.
Two more gene regions have been linked this week to late-onset Alzheimer's disease. To date, scientists have identified three autosomal dominant genes linked to early-onset Alzheimer's disease and a susceptibility gene on chromosome 19, apolipoprotein E (APOE). The APOE-4 allele has been linked to early-onset sporadic disease and to familial and sporadic late-onset disease. Together, however, these genes explain only about 50% of the genetic component of Alzheimer's disease aetiology.
In the USA, researchers have now homed in on a region of chromosome 12. Senior author Jonathan Haines (Vanderbilt University, Nashville, TN, USA) said, "There might be loci of interest on the other chromosomes, but this one popped up in our study".
Meanwhile, in the UK, another genetic risk factor for late-onset disease was reported by David Smith (Oxford University, Oxford, UK) and co-workers. People more than 65 years old carrying the K variant of the gene for butyrylcholinesterase (on chromosome 3) as well as the APOE-4 allele have a 30-fold increased risk of developing Alzheimer's disease compared with people who carry neither genetic variant
J Neuropathol Exp Neurol 1997 Oct;56(10):1119-1124 Guentchev M, Hainfellner JA, Trabattoni GR, Budka HThere is a distinctive pattern of hippocampal involvement in Creutzfeldt-Jakob disease (CJD) and evidence for selective vulnerability of GABAergic neurons in experimental and human prion disease. We studied hippocampus and temporal cortex from human CJD and control autopsy brains and surgical cryptogenic temporal lobe epilepsy specimens for distribution and density of parvalbumin (PV) and calbindin-D28K (Cal) -positive neurons that are subpopulations of GABAergic neurons. Pathology was evaluated semiquantitatively in 8 regions in 23 CJD brains for severity of spongiform change, astrogliosis and pathological prion protein deposition. In CJD, pathology was severe in pre-parasubiculum and temporal cortex, and little or absent in CA1-4; PV+ neurons were severely reduced or absent in all cases, whereas Cal+ neurons were largely preserved. In controls, the density of PV+ neurons was highest in pre-parasubiculum and temporal cortex, and lowest in CA1-4. In cTLE, loss of PV+ neurons was seen only in CA1-4. The diffuse and severe loss of PV+ neurons in CJD, and the topographical correlation of tissue lesioning in CJD with density of PV+ neurons in controls suggest selective vulnerability and early loss of this subset of inhibitory neurons in CJD. This might relate to characteristic CJD symptoms such as myoclonus and the distinctive EEG pattern.
Ann N Y Acad Sci 1997 Sep 26;826:390-395 Cohen DL, Hedera P, Premkumar DR, Friedland RP, Kalaria RNCurrent evidence from genetic and epidemiological studies supports the view that Alzheimer's disease (AD) is a heterogeneous disorder. While the disease is pathologically defined by the presence of specified lesions in form of amyloid plaques and neurofibrillary tangles within the parenchyma, other features of pathology are often either neglected or considered coincidental. Our studies suggest that cerebrovascular pathology is inherently part of the disorder, which could be an important factor in a cause or effect manner. We have recently identified subjects having died with severe amyloid beta (A beta) protein cerebral amyloid angiopathy (CAA) in the absence of a profound Alzheimer pathology. These subjects, diagnosed with dementia had a late onset disease and were found at autopsy to exhibit severe CAA but paucity of typical AD changes. Immunocytochemical studies showed numerous microvascular abnormalities as well as characteristic degeneration of the vascular smooth muscle in both surface and intracortical vessels. The pathology was also characterized by occasional intracerebral hemorrhages and multiple infarcts. Further assessment of the abnormalities and amyloid infiltrated cerebral vessels with antibodies to the carboxyl terminus of A beta indicated that the longer, more pathogenic form of A beta(1-42) was found to be highly associated with intracerebral hemorrhages. Our observations suggest that these mild AD cases with a predominantly vascular pathology are variants of AD and bear resemblance to the familial Dutch and Flemish versions of cerebral amyloidosis. We propose that AD is a group of diseases with a variable pathology analogous to the prion diseases, in which a vascular variant also exists.
Wisniewski HM, Vorbrodt AW, Wegiel J Ann N Y Acad Sci 1997 Sep 26;826:161-172Evidence is accumulating that suggests that increased permeability of the BBB to blood-borne proteins is favorable for the development of neuropathologic changes such as amyloid angiopathy and formation of amyloid plaques in the AD brain. To study this problem, we applied a quantitative immunocytochemical procedure that enables evaluation of the barrier function of brain microvasculature to endogenous albumin. This procedure was successfully used on scrapie-infected mice, which represent a unique animal model enabling study of an interrelation between BBB function and deposition of amyloid within vascular wall and neuritic plaques. Biopsy specimens obtained during neurosurgical procedures (tumors and dementia) were also examined. Our observations indicate that (1) the vast majority of brain microvessels in scrapie-infected mice and in demented individuals show normal features of the BBB; (2) only those microvascular segments directly surrounded by amyloid plaques or representing amyloid angiopathy show increased permeability to endogenous albumin; (3) numerous immunosignals over the amyloid deposits in plaques and in the wall of angiopathic vessels suggest the affinity of extravasated albumin to the amyloid material.
Komar AA, Lesnik T, Cullin C, Guillemet E, Ehrlich R, Reiss C FEBS Lett 1997 Sep 22;415(1):6-10The Ure2p yeast prion-like protein was translated in vitro in the presence of labeled [35S]methionine in either rabbit reticulocyte lysate (RRL) or wheat germ extract (WGE) cell-free systems. When subjected to proteinase K digestion, the Ure2p protein synthesized in WGE was proteolysed much more slowly compared to that synthesized in RRL; this displays fragments of about 31-34 kDa, persisting over 8 min. Thus, the digestion rate and pattern of the protein synthesized in WGE, unlike that synthesized in RRL, revealed characteristic features of the [URE3] prion-like isoform of the Ure2p protein [Masison, D.C. and Wickner, R.B. (1995) Science 270, 93-95]. Chloramphenicol acetyltransferase, synthesized under the same conditions, differed fundamentally in its proteolytic sensitivity toward proteinase K (PK); in the RRL system it was more slowly digested than in WGE, proving specific PK inhibitors to be absent in both systems. Posttranslational addition of the WGE to the RRL-synthesized Ure2p does not protect Ure2p from efficient PK degradation either. The differences in Ure2p degradation may be ascribed to a specific structure or specific states of association of Ure2p synthesized in WGE; obviously, they yield a protein that mimics the behavior of the Ure2p in [URE3] yeast strains. The present data suggest that particular conditions of the Ure2p protein translation and/or certain cellular components (accessory proteins and extrinsic factors), as well as the nature of the translation process itself, could affect the intracellular folding pathway of Ure2p leading to the de novo formation of the prion [URE3] isoform.
Baron T, Belli P, Madec JY, Moutou F, Vitaud C, Savey M Vet Rec 1997 Sep 13;141(11):270-271
MacGowan DJ, Delanty N, Petito F, Edgar M, Mastrianni J, DeArmond SJ J Neurol Neurosurg Psychiatry 1997 Sep;63(3):404-407Creutzfeldt-Jakob disease may have many atypical presentations before the development of classic progressive dementia and startle myoclonus. In two patients with pathologically established disease association with a progressive alien hand syndrome was the sole initial manifestation of the disease.
Heckmann JG, Lang CJ, Petruch F, Druschky A, Erb C, Brown P, Neundorfer B J Neurol Neurosurg Psychiatry 1997 Sep;63(3):388-390A 45 year old woman is reported who initially presented with a cerebellar syndrome, severe ataxia, and dysarthria. She rapidly deteriorated to coma vigile with bilateral myoclonic jerks, flexion rigidity, and immobility necessitating complete nursing. Her EEG showed generalised slow activity and periodic biphasic and triphasic waves. The CSF concentration of neuron specific enolase was very high. Consequently the diagnosis of Creutzfeldt-Jakob disease was established. Eight months later she died of respiratory complications. Thirty years earlier the patient had undergone corneal transplantation for keratoconus. Review of the organ donor's hospital records showed that death was caused by intercurrent pneumonia subsequent to subacute spongiform encephalopathy confirmed by necropsy. In view of two previous case reports in the literature it is presumed that the cadaveric cornea was the source of transmission of Creutzfeldt-Jakob disease in this patient.
Schreuder BE, van Keulen LJ, Smits MA, Langeveld JP, Stegeman JA Vet Q 1997 Sep;19(3):105-113After a brief description of the scrapie situation in the Netherlands, the technical progress made in aspects of scrapie diagnosis is reported. Emphasis is placed on the use of immuno-histochemistry (IHC) in the post-mortem histological diagnosis and on the recently published preclinical test for scrapie, in which IHC is applied to tonsillar biopsies. These two approaches use the same IHC technique and enable us to confirm suspected scrapie in individual animals, and for certain genotypes even in the preclinical phase. The tonsillar biopsy method could eventually lead to an infection- or PrPSc-detection method at flock level. Further work is required, including validation of the assay for various breeds, genotypes, and strains of the agent, and the conversion of the test into a more practical assay. The article continues with a discussion of several scrapie control strategies, describing briefly schemes tried in various countries, and elaborates on a proposed scrapie control scheme that could be suitable for the Netherlands. This scheme is essentially based on breeding for resistance, based on PrP genotyping.
Vet Q 1997 Sep;19(3):101-105 Smits MA, Bossers A, Schreuder BEThis article presents briefly current views on the role of prion protein (PrP) in Transmissible Spongiform Encephalopathies or prion diseases and the effect of PrP polymoryhisms on the susceptibility to these diseases, with special emphasis on sheep scrapie. The PrP genotype of sheep appears to be a major risk factor for scrapie, and polymorphisms at codons 136, 154, and 171 modulate the susceptibility of sheep for scrapie. Nevertheless, scrapie is not a spontaneous genetic disease alone. We describe an in vitro system in which sheep PrP variants show characteristics which reflect their linkage with in vivo scrapie susceptibility. Studies with this in vitro system not only confirm that scrapie susceptibility is determined by the PrP genotype of the target animal, but also suggest that the PrP genotype of the animal that is the source of the infectious agent plays an important role in determining scrapie susceptibility. The behaviour of PrP variants in this in vitro system may be an indicator for the transmissibility of prion diseases.
Neurology 1997 Sep;49(3):851-856 Rosenmann H, Halimi M, Kahana I, Biran I, Gabizon RCreutzfeldt-Jakob disease (CJD) linked to the E200K mutation of the prion protein (PrP) gene presents with a wide range of age at disease onset. Since most patients are heterozygous for the mutation, we tested whether differential expression of mutant versus wild-type (wt) PrP may affect the age at disease onset in carriers of the mutation. We measured wt and mutant PrP protein and mRNA in Epstein-Barr virus (EBV)-transformed B cells of either E200K CJD patients or healthy E200K carriers. Our results suggests that while in most healthy carriers the expression of wt PrP was higher than that of E200K PrP, most of the E200K CJD patients express equal levels of both PrP proteins. Similar results were obtained for either PrP protein or PrP mRNA. These results suggest that preferential expression of PrP from the wt allele may modulate the outbreak of the disease in carriers of prion mutations. This notion is consistent with the results obtained in transgenic mice carrying a human PrP gene, which suggest that endogenous PrP protects mice from contracting scrapie after inoculation with human CJD brain. Similar mechanisms may prevail in other inherited diseases with variable phenotypes.
Nat Med 1997 Sep;3(9):1009-1015 Chen SG, Parchi P, Brown P, Capellari S, Zou W, Cochran EJ, Vnencak-Jones CL, Julien J, Vital C, Mikol J, Lugaresi E, Autilio-Gambetti L, Gambetti PThe hallmark of prion diseases is the presence of an aberrant isoform of the prion protein (PrP(res)) that is insoluble in nondenaturing detergents and resistant to proteases. We investigated the allelic origin of PrP(res) in brains of subjects heterozygous for the D178N mutation linked to fatal familial insomnia (FFI) and a subtype of Creutzfeldt-Jakob disease (CJD178), as well as for insertional mutations associated with another CJD subtype. We found that in FFI and CJD178 subjects, only mutant PrP was detergent-insoluble and protease-resistant. Therefore, PrP(res) derives exclusively from the mutant allele carrying the D178N mutation. In contrast, in the CJD subtype harboring insertional mutations, wild-type PrP was also detergent-insoluble and likely to be protease-resistant. Our findings indicate that the participation of the wild-type PrP in the formation of PrP(res) depends on the type of mutations, providing an insight into the molecular mechanisms underlying the phenotypic heterogeneity in familial prion diseases.
J Immunol Methods 1997 Aug 22;207(1):89-101 Groschup MH, Harmeyer S, Pfaff EPathological prion protein (PrPSc) which is a conformational isoform of a host-encoded protein designated (PrPC) serves as a specific marker protein for the immunochemical diagnosis of transmissible spongiform encephalopathies (TSE). The generation of suitable antibodies to PrPSc therefore underlies the specificity and sensitivity of diagnostic assays. However, most antibodies reported to date are directed to a limited number of epitopes only. PrPC is a highly conserved cell membrane protein in all mammalian species studied to date. In an attempt to generate antibodies to further regions of PrP we raised antisera in rabbits and chicken against sixteen synthetic peptides which represent the complete aminoacid sequence of ovine PrP. By this approach immunotolerance was overcome and immunoblot-reactive antibodies were stimulated to epitopes at almost any site of ovine PrPC and PrPSc. A large number of different antibodies cross-reacted also with affinity-purified PrPCs from other mammalian species including cow, goat, pig, man, dog, cat, mink, mouse, hamster and guinea pig. No epitope, however, was recognized exclusively on the pathological or cellular isoform of PrP indicating that both isoforms occur in highly denatured conformations on the immunoblots. Antibodies to the amino-terminus are suitable for immunoprecipitation of PrP. The availability of rabbit and chicken anti-peptide antibodies to PrP will greatly improve immunochemical diagnosis and pathogenetic studies on these diseases.