Gareth W. Roberts

A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene

A series of mutations has been reported in the presenilin-1 (PS-1) gene which cause early onset Alzheimers disease (AD). The mutations reported to date have encoded missense mutations which alter residues conserved between PS-1 and the presenilin-2 (PS-2) gene. We have recently determined the intron/exon structure of the PS-1 gene and this information has been used to identify a mutation in the splice acceptor site for exon 9 in a family with early onset AD. Amplification of cDNA from lymphoblasts of affected individuals revealed that the effect of the mutation was to cause splicing out of exon 9, however it does not change the open reading frame of the mRNA. The importance of this observation is discussed.

Peptides, the limbic lobe and schizophrenia

The human brain contains several peptides with probable synaptic actions, some of which form complex neuronal networks in the limbic lobe (amygdala, hippocampus and temporal cortex). A limbic lobe abnormality has been postulated in schizophrenia on the basis of similarities between schizophrenic symptoms and symptoms in cases of known limbic pathology. Cholecystokinin (CCK), somatostatin (SRIF), neurotensin (NT), vasoactive intestinal polypeptide (VIP) and substance P (SP)-like immunoreactivities were measured by radioimmunoassay in 10 brain areas of 14 schizophrenics and 12 controls. In the schizophrenic group symptoms had been rated in life and the group was divided into Type I (n = 7) and Type II (n = 7) subgroups on the basis of the absence or presence of morbid negative symptoms. In control brains each peptide showed a characteristic distribution with high levels in cortex (CCK), limbic lobe (SOM, NT, VIP) or striatal areas (SP) and low levels of each of the peptides in thalamus. Significant (P less than 0.05) differences between groups were: reductions of CCK and SOM in hippocampus and CCK in amygdala in Type II schizophrenics, and CCK in the temporal cortex of the total schizophrenic group; and elevations of VIP in amygdala in Type I schizophrenics and of SP in the hippocampus in the total schizophrenic group. The findings could not be explained by variables such as age, delay between death and necropsy or to neuroleptic medication. These clinical-state related alterations in the peptide content of the limbic system in schizophrenia may illuminate the pathophysiological basis of the disease, particularly the distinction between Type I and II syndromes.

Reduced cholecystokinin-like and somatostatin-like immunoreactivity in limbic lobe is associated with negative symptoms in schizophrenia

Cholecystokinin-like immunoreactivity (CCK) and somatostatin-like immunoreactivity (SRIF) were determined in fourteen brains from patients dying with a diagnosis of schizophrenia and in twelve brains from control cases. The schizophrenics had been rated during life and were divided into two groups on the basis of the presence or absence of negative symptoms (affective flattening and poverty of speech). CCK was reduced in temporal cortex of the schizophrenics and in hippocampus and amygdala of those patients with negative symptoms. SRIF was reduced in the hippocampus in samples from the latter group. The selectivity of these changes to limbic lobe may reflect the presence of a degenerative process in that area. The association of changes in hippocampus and amygdala with negative symptoms of schizophrenia suggests a separate mechanism underlying these symptoms.

Is there gliosis in schizophrenia? Investigation of the temporal lobe

Recent studies have described two indicators of pathology in the schizophrenic brain--gliosis and atrophy. The degree of gliosis in the temporal lobe of groups of schizophrenics (with demonstrable atrophy), affectives, and controls was quantified using immunocytochemical techniques and computer-assisted densitometry. Twenty areas within the temporal lobe were assessed. Our data showed no evidence of increased gliosis in the schizophrenic group compared to controls and affectives. This extends and replicates our previous findings, demonstrating that the atrophy/aplasia in schizophrenia is not associated with pathologically significant gliosis. Our observations are consistent with other studies, suggesting that the structural change in schizophrenic brains is due to an embryonic insult or developmental anomaly of an, as yet, undetermined nature.

A "mock up" of schizophrenia: temporal lobe epilepsy and schizophrenia-like psychosis.

Schizophrenia-like psychoses occur more frequently than expected in patients with chronic temporal lobe epilepsy. We have analyzed pathological and clinical data from a series (n = 249) of temporal lobectomies to determine the factors that may relate to the development of schizophrenia-like psychosis. Schizophrenia-like psychoses did not occur at random; they were significantly associated with lesions that (1) originated in the fetus or perinatally, (2) affected neurons in the medial temporal lobe, and (3) gave an early age of first fit. Gangliogliomas--developmental lesions of the medial temporal lobe containing aberrant neurons--were disproportionately (p less than 0.001) associated with risk of psychosis. Schizophrenia-like psychoses arising preoperatively occurred more often (p = 0.1) with left-sided lesions. Asymmetry of lesion was not present in cases with postoperative psychoses. These findings are of interest in relation to recent studies suggesting that the structural abnormalities found in the brains of schizophrenics arise during fetal brain development.

Schizophrenia: the cellular biology of a functional psychosis

Structural abnormalities are found in the brains of schizophrenics. They affect preferentially, but not exclusively, medial temporal lobe structures (parahippocampal gyrus, hippocampus and amygdala), and can be found in all sub-types of schizophrenia. The structures of the medial temporal lobe are believed to have a crucial role in the integration and processing of the output from association cortex. It is probable that all schizophrenics have abnormalities in the medial temporal lobe that differ in degree but not in kind. Dysfunction of this system could result in the clinical symptoms that form the core of the schizophrenia syndrome. The changes in brain structure are not the result of neurodegenerative processes or destructive lesions but suggest a disturbance in the normal pattern of brain development.

Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease

The presenilin 1 gene has recently been identified as the locus on chromosome 14 which is responsible for a large proportion of early onset, autosomal dominantly inherited Alzheimers disease (AD). We have elucidated the intron/exon structure of the gene and designed intronic primers to enable direct sequencing of the entire coding region (10 exons) of the presenilin gene in a large number of families. This strategy has enabled us to find a further two novel mutations in the gene. We discuss the distribution of mutations and the proportions of autosomal dominant AD with a mean age of onset below 60 years caused by mutations in this gene.

Distribution of galanin-like immunoreactivity in the human brain

The distribution of galanin-like immunoreactivity has been studied in complete coronal sections taken from 9 normal human brains (4 male, 5 female mean age 54, range 42-72 years). Galanin-immunoreactive cells were restricted largely to the basal nucleus of Meynert and to the supraoptic, ventromedial and posterior areas of the hypothalamus. Fibre staining was more widespread, seen throughout the hypothalamus and in the diagonal band, septum, amygdala, hippocampus and scattered throughout the cortex. This distribution may indicate a role for galanin in the modulation of hypothalamic and basal forebrain function in man.

Chapter 16 Molecular pathology of head trauma: altered βAPP metabolism and the aetiology of Alzheimer's disease

Publisher Summary Considerable progress has been made in determining the identity of the proteins and molecular events involved in the molecular pathology of Alzheimers disease (AD), the most widely known of which are the inevitability of Alzheimers disease in Downs syndrome patients with trisomy of chromosome 21 and the point mutations at codon 717 within exon 17 of the β -amyloid precursor protein gene on chromosome 21. However, these genetic causes of Alzheimers disease account for a vanishingly small proportion of patients who suffer from the disease. It is probable that the overwhelming majority of cases are caused by a variety of environmental factors, which may be either sufficient to trigger disease by themselves or sufficient when acting synergistically with the patients genotype. One of the best-documented environmental precipitants of Alzheimers disease is a previous history of head trauma. AD can be caused by a variety of factors. Approximately 20% of AD cases are thought to be familial with almost 5% exhibiting an autosomal dominant pattern of inheritanc. Screening of the amyloid precursor protein ( β APP) gene on chromosome 21, which gives rise to the β -amyloid protein found in plaques, has revealed a mutation in some AD families.

ALZHEIMER'S DISEASE-ASSOCIATED PRESENILIN 1 IN NEURONAL CELLS : EVIDENCE FOR LOCALIZATION TO THE ENDOPLASMIC RETICULUM-GOLGI INTERMEDIATE COMPARTMENT

The recently identified Alzheimers disease‐associated presenilin 1 and 2 (PS1 and PS2) genes encode two homologous multi membrane‐spanning proteins. Rabbit antibodies to the N‐terminal domain of PS1 detected PS1 in human neuroblastoma SH‐SY5Y wild type and PS1 transfectants (SY5Y‐PS1) as well as in mouse P19, in CHO‐K1 and CHO‐APP770 transfected cells, in rat cerebellar granule and hippocampal neurons, and astrocytes. Immunoblotting detected full‐length protein of 50 kDa, and a major presumptive cleavage product of 30 kDa. The immunofluorescence pattern resembled labeling of the endoplasmic reticulum‐Golgi intermediate compartment (ERGIC) marker protein ERGIC‐53. PS1 distribution showed slight condensation after brefeldin A and more marked condensation after incubation of cells at 16°C, characteristic of the ERGIC compartment. Double labeling showed colocalization of ERGIC‐53 with PS1 in the SY5Y‐PS1 cells. PS1 labeling of SY5Y‐PS1 and P19 cells showed overlap of the cis‐Golgi marker p210 and colocalization with p210 after brefeldin A which causes redistribution of p210 to the ERGIC. Expression of PS1 did not change in level or cellular distribution during development of neurons in culture. Double labeling for the amyloid precursor protein (APP) and PS1 on SY5Y‐PS1 cells and CHO‐APP770 cells showed some overlap under control conditions. These results indicate that PS1 is a resident protein of the ERGIC and could be involved in trafficking of proteins, including APP, between the ER and Golgi compartments. J. Neurosci. Res. 49:719–731, 1997.