Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14.

Familial Alzheimer's disease (FAD) has been shown to be genetically heterogeneous, with a very small proportion of early onset pedigrees being associated with mutations in the amyloid precursor protein (APP) gene on chromosome 21, and some late onset pedigrees showing associations with markers on chromosome 19. We now provide evidence for a major early onset FAD locus on the long arm of chromosome 14 near the markers D14S43 and D14S53 (multipoint lod score z = 23.4) and suggest that the inheritance of FAD may be more complex than had initially been suspected.

Electrotonic spread of dendritic potentials in feline pyramidal cells.

In pyramidal cells synaptic activation of the entire apical dendritic tree distal to the branch point of the major shaft can dominate the neuronal firing pattern. Uniform synaptic activation of distant parts of the dendritic tree (~ 750 microns from the soma) would produce potential changes at the soma of 2 to 3 percent of the magnitude of the dendritic potential changes. Even these small somatic potential changes could modulate the frequency of firing of neurons depolarized close to or above firing level by more proximal synaptic inputs.

Phase relationships between adjacent simple cells in the visual cortex.

Adjacent simple cells recorded and "isolated" simultaneously from the same microelectrode placement were usually tuned to the same orientation and spatial frequency. The responses of the members of these "spatial frequency pairs" to drifting sine-wave gratings were cross-correlates. Within the middle range of the spatial frequency selectivity curves, the responses of the paired cells differed in phase by approximately 90 percent. This phase relationship suggests that adjacent simple cells tuned to the same spatial frequency and orientation represent paired sine and cosine filters in terms of their processing of afferent spatial inputs and truncated sine and cosine filters in terms of the output of simple cells.

Electrical recordings from meningioma cells during cytolytic action of antibody and complement.

Resting membrane potential and total cell resistance of human meningioma cells in tissue culture have been measured with fine microelectrodes. Addition of either antiserum inactivated with heat or control serum from normal rabbits produced small depolarizations (2 to 4 millivolts) with no discernible ( 5 percent) change in resistance. Addition of antiserums with complement, however, produced larger depolarizations and decreases in resistance before any changes in cell morphology were visible with light microscopy; as cytoplasmic swelling progressed, membrane potential dropped close to zero, and resistance decreased five- to tenfold. The electrical recording technique may be useful in the study of sublethal as well as lethal damage to immune cells and, in particular, may permit temporal resolution of damaging events and repair mechanisms in a single cell.

Neuroglia: gliosis and focal epilepsy.

Normal neuroglial cells buffer the extracellular space around neurons and presynaptic terminals against increases in potassium ions. Epileptic foci resulting from brain injury are characterized by areas of intense fibrillary gliosis bordering neuronal tissue. The known pathological changes that occur in gliosis may impair glial control of extracellular potassium ions and lead to excessively excitable neuronal border regions.

Neuroglia: biophysical properties and physiologic function.

The membrane time constant of neocortical glial cells is abolut 385 microseconds, less than one-twentieth the known value for the Betz cell. Glial membrane specific resistance is low (approximately 200 to 500 ohm centimeters squared. Neuroglial cells are ideally suited to buffer the immediate extraneuronal space at areas of synaptic contact against the increases in external potassium ion concentration that accompany postsynaptic and spike activity and to minimize the spread of potassium ions to other pre- and postsynaptic regions.

How does the striate cortex begin the reconstruction of the visual world?

The striate cortex transforms the topographic representation of visual space in the lateral geniculate body into a Fourier transform or frequency representation at the complex cell level via the intermediary simple cell stage of "strip integration." Each of these three stages contains essentially the same amount of information, which expresses a conservation of information principle; however, the form of the information is changed. In the transform domain, invariant descriptions of visual objects can be derived to serve as the basic sets required for pattern recognition and memory. We believe that our experimental and theoretical findings are fundamental for understanding the functional organization of the striate cortex.

Absence of duplication of chromosome 21 genes in familial and sporadic Alzheimer's disease.

The possibility that Alzheimer's disease (AD) is caused by overexpression or duplication of one or more genes on chromosome 21 has been raised by the observation of AD-like neuropathologic changes in individuals with Down syndrome and by the mapping of both the defect for familial AD and the amyloid beta protein gene to this autosome. Possible duplication on chromosome 21 was investigated in both familial and sporadic AD by means of restriction fragment length polymorphisms for the amyloid and SODI loci, as well as for DNA markers in the vicinity of the familial AD defect and in the critical Down syndrome region of chromosome 21. No evidence of increased DNA dosage was observed in either brain or leukocytes of patients with inherited or sporadic forms of AD. Duplication of these regions is therefore not a frequent event in either form of AD. Furthermore, no significant allelic association was detected between AD and any of the loci, including the amyloid and SODI genes, providing no support for the hypothesis that defects in these specific genes are the primary cause of AD.

The genetic defect causing familial Alzheimer's disease maps on chromosome 21.

Alzheimer's disease is a leading cause of morbidity and mortality among the elderly. Several families have been described in which Alzheimer's disease is caused by an autosomal dominant gene defect. The chromosomal location of this defective gene has been discovered by using genetic linkage to DNA markers on chromosome 21. The localization on chromosome 21 provides an explanation for the occurrence of Alzheimer's disease-like pathology in Down syndrome. Isolation and characterization of the gene at this locus may yield new insights into the nature of the defect causing familial Alzheimer's disease and possibly, into the etiology of all forms of Alzheimer's disease.

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.

Altered expression of transforming growth factor-beta in Alzheimer's disease.

We compared immunohistochemical expression of the transforming growth factor-betas (TGF-beta 1, TGF-beta 2, and TGF-beta 3) using brain tissue from patients with nondominantly inherited Alzheimer's disease (NDAD) (n = 9), autosomal dominantly inherited Alzheimer's disease with linkage to 14q24.3 (FAD-14) (n = 4), and cognitively normal controls (n = 10) to determine whether their pathologic changes are associated with an altered distribution of the TGF-betas. We found increased expression of TGF-beta 2 in large, tangle-bearing neurons with widespread staining of glia in NDAD and FAD-14 patients compared with control cases. This result was confirmed with sandwich ELISA assays of brain tissue, which showed TGF-beta 2 levels in AD and NDAD to average 3.2 times the average level of control cases. Despite proximity of TGF-beta 1 and TGF-beta 3 to the sites of susceptibility loci on chromosomes 19 and 14, we did not find that TGF-beta 1 and TGF-beta 3 were selectively altered in any AD subtypes. However, selective induction of TGF-beta 2 may occur in NDAD and FAD-14.

Familial and sporadic Alzheimer's disease: neuropathology cannot exclude a final common pathway.

Whether all etiologic forms of Alzheimer's disease (AD) share a final common pathway is a major issue. We determined the severity and regional distribution of neuronal loss, amyloid plaques, neuritic plaques (NPs), and neurofibrillary tangles (NFTs), and calculated the ratio of neuronal loss to NPs and NFTs in brains of 19 familial AD (FAD) patients with linkage to chromosome 14, six AD patients with mutations of chromosome 21 (codon 717 of the beta-amyloid percursor protein gene), and 11 sporadic AD (SAD) patients. There was no difference in the pattern of distribution of the various pathologic features or in the ratio of neuronal loss to NPs or NFTs in any AD group. However, FAD groups could be distinguished from SAD by the greater severity and the lack of influence of apolipoprotein E genotype on pathology. These differences may reflect differences in age at onset rather than different etiopathologic mechanisms. The similarity of pathologic findings in the different AD groups provides evidence for a final common pathophysiologic pathway in AD.

Analysis of the c-FOS gene on chromosome 14 and the promoter of the amyloid precursor protein gene in familial Alzheimer's disease.

The c-FOS gene product, a putative transacting transcriptional regulator of the amyloid precursor protein (APP) gene, is a candidate locus for the familial Alzheimer's disease (FAD) mutation on chromosome 14 (FAD14). In light of this functional relationship, we investigated the nucleotide sequence and segregation of c-FOS and the nucleotide sequence of the 5' APP promoter. Single-stranded conformational polymorphisms (SSCPs) in the c-FOS gene revealed that c-FOS closely cosegregates with the FAD14 gene but does not show allelic association with FAD. A conservative third-position T-->C mutation was demonstrated in exon 2 (codon 84) of c-FOS, and a C-->G substitution was detected at -209 bp in the 5' promoter of APP. Neither were unique to FAD and are unlikely to be pathogenic or secondary modifiers of the FAD phenotype. We conclude that the c-FOS open reading frame is probably not the site of the FAD14 locus, but we cannot exclude the existence of modifier loci on chromosome 21.

Spatial periodicities of periodic complex cells in the visual cortex cluster at one-half octave intervals.

Within individual penetrations in the visual cortex, spatial periodicities of periodic complex cells differ by either one-half or one octave. When data are pooled from neurons subserving the central visual area in many cats, the results indicate that spatial periodicities cluster at one-half octave intervals over a 2 1/2-octave range (0.95 to 5.4 cyc/deg). Thus a relatively small number of such channels spaced at regular intervals along a logarithmic scale within each orientation column may suffice for this stage of spatial processing.

Amyloid-beta-protein isoforms in brain of subjects with PS1-linked, beta APP-linked and sporadic Alzheimer disease.

To determine whether similar abnormalities of various soluble full-length and N-terminal truncated Abeta peptides occur in postmortem cerebral cortex of affected PS1 mutation carriers, we examined the amounts of two amyloid species ending at residue 40 or at residues 42(43) using sandwich ELISA systems. Our results indicate that PS1 mutations effect a dramatic accumulation in brain of the highly insoluble potentially neurotoxic long-tailed isoforms of the Abeta peptide such as Abeta1-42(43) and Abetax-42(43). This enhancing effect of PS1 mutation on Abetax-42(43) deposition was highly similar to that of a betaAPP mutation (Val717Ile) but the effects on Abetax-40 production were significantly different between these two causal genes. In contrast to previous studies of soluble Abeta in plasma and in supernatants from cultured fibroblasts of subjects with PS1 mutations, our studies also show that there is an increase in insoluble Abetax-40 peptides in brain of subjects with PS1 mutations.

Postmenopausal hormone therapy and cognitive function in healthy older women.

OBJECTIVE: Accumulating biologic evidence suggests that estrogen is related to cognitive function. Several epidemiologic investigations have reported that hormone therapy may reduce the risk of Alzheimer's disease. However, fewer studies have examined the relation of postmenopausal hormone use to general cognitive function in nondemented older women. Thus, we examined the association of hormone therapy to performance on four cognitive tests among healthy participants of the Nurses' Health Study. DESIGN: Cohort study. SETTING: The Nurses' Health Study, an ongoing prospective cohort study begun in 1976. PARTICIPANTS: From the Nurses' Health Study, 2138 women aged 70-78 years. MEASUREMENTS: From 1995-1999 we administered four cognitive tests (Telephone Interview for Cognitive Status (TICS), immediate and delayed recall of the East Boston Memory Test (EBMT), and verbal fluency) by telephone. Hormone use was ascertained from biennial questionnaires beginning in 1976. Linear and logistic regression models were used to calculate multivariate-adjusted differences in scores and relative risks of a low score for never users compared to current and past hormone users. RESULTS: After adjustment for confounders, neither current nor long-term hormone users demonstrated better performance on an overall measure of cognition (TICS), or on three tests of verbal memory (immediate and delayed recall of the EBMT, immediate recall of the TICS 10-word list) than never users. On the test of verbal fluency, current hormone users scored significantly better than never users (linear regression estimate of the difference in score = 0.78 points, 95% confidence interval (CI) 0.19-0.38, P = .01 for any current use; and 0.91 points, 95% CI 0.28-1.54, P = .005 for > or = 5 years current use). Current hormone users also had a 30% decrease (RR = 0.70, 95% CI 0.45-1.09) in their risk of a low score on the test of verbal fluency. These results were similar for women taking estrogen alone and estrogen combined with a progestin. CONCLUSIONS: Verbal fluency may be enhanced among women taking postmenopausal hormones, however, there is little support for better overall cognitive function in hormone users than nonusers.

Responses of complex cells in the visual cortex of the cat as a function of the length of moving slits.

(1) As a step towards specifying the spatial selectivity characteristics of complex cells with spatially periodic substructures, we have studied single cell responses to narrow slits of variable length moved across the receptive field in the preferred direction. In general, the length-response curves were linear over a considerable and sometimes full range until an optimal slit length was reached. (2) In those cells in which the rate of rise of the slit length-response functions decreased before the optimal length was reached, at least 3 factors contribute to the shape of the curve. First, the receptive field shapes of some complex cells are more ovoid or rounded than rectangular, and the summation of responses from excitatory zones of varying optimal lengths itself results in a nonlinear slit length-response function at long slit lengths. Second, central regions may contribute more to cell response than do more lateral regions along the length dimension. Third, a nonlinearity in the slit length-response curve may occur in the upper range of slit lengths as a saturation effect because discharge rates may reach 600/sec, which appears to be close to a limiting firing rate. (3) Some cells believed to be complex during preliminary receptive field testing showed weak inhibitory regions beyond the region of the optimal slit length. Many of these cells also displayed periodic average response histograms to moving slits. The extent and magnitude of the inhibition were variable from cell to cell. In terms of receptive field properties, these cells and 'regular' complex cells seem part of a continuum.

Failure to detect missense mutations in the S182 gene in a series of late-onset Alzheimer's disease cases.

The possibility of an interaction of multiple genes has been speculated in pathogenesis of Alzheimer's disease (AD). Because we have recently cloned a novel gene S182 bearing five different missense mutations which segregate with early-onset familial AD, we sought the frequency of these mutations in familial and sporadic late-onset AD to clarify the incidence of these mutations in the disease. The current study showed lack of these mutations in 118 independent subjects affected with late-onset Alzheimer's disease.