Alzheimer's Disease/senile Dementia Of The Alzheimer Type Research Articles

Emerging concepts in Alzheimer's disease.

Alzheimer's disease/senile dementia of the Alzheimer type (AD/SDAT) is the most common neuropathologic substrate of dementia. It is characterized by synapse loss (predominantly within neocortex) as well as deposition of certain distinctive lesions (the result of protein misfolding) throughout the brain. The latter include senile plaques, composed mainly of an amyloid (Aβ) core and a neuritic component; neurofibrillary tangles, composed predominantly of hyperphosphorylated tau; and cerebral amyloid angiopathy, a microangiopathy affecting both cerebral cortical capillaries and arterioles and resulting from Aβ deposition within their walls or (in the case of capillaries) immediately adjacent brain parenchyma. In this article, I discuss the hypothesized role these lesions play in causing cerebral dysfunction, as well as CSF and neuroimaging biomarkers (for dementia) that are especially relevant as immunotherapeutic approaches are being developed to remove Aβ from the brain parenchyma. In addition, I address the role of neuropathology in characterizing the sequelae of new AD/SDAT therapies and helping to validate CSF and neuroimaging biomarkers of disease. Comorbidity of AD/SDAT and various types of cerebrovascular disease is a major theme in dementia research, especially as cognitive impairment develops in the oldest old, who are especially vulnerable to ischemic and hemorrhagic brain lesions.

Adenylyl cyclase activity in Alzheimer's disease brain: stimulatory and inhibitory signal transduction pathways are differently affected

Adenylyl cyclase (AC) activity was studied in post mortem hippocampus and cerebellum from eight patients with Alzheimer's disease/senile dementia of the Alzheimer type (AD/SDAT) and seven non-demented control patients. AC was stimulated via stimulatory guanine nucleotide binding proteins (Gs) using guanosine triphosphate (GTP) and GppNHp (both 10 −4M) or directly with either forskolin (10 −4M) or Mn 2+ (10 −2M). Inhibition of AC via A 1-receptors was performed with N 6-cyclohexyladenosine (CHA) under basal conditions and in the presence of forskolin (10 −5M). In both brain regions AC activity was significantly reduced in AD/SDAT when compared to controls. Under basal conditions and after stimulation via Gs mean reduction in hippocampus and cerebellum was 47.7% and 58.2%, respectively. The reduction was less pronounced after direct activation of the AC, amounting to 21.8% in hippocampus and 28.1% in cerebellum. CHA inhibited basal and forskolin-stimulated AC concentration-dependently by about 20% (basal) and 30% (forskolin). Inhibition by CHA was similar in hippocampus and cerebellum and tended to be more pronounced in AD/SDAT than in controls. Since the reduction of AC activity in AD/SDAT is greater after stimulation via Gs than after direct activation of the catalytic subunit, we suggest that both Gs and the catalytic subunit seem to be impaired. The fact that CHA-mediated inhibition of AC is not significantly different in AD/SDAT and controls, indicates that in contrast to Gs-, inhibitory G-proteins (Gi) coupling to AC remains intact in Alzheimer's disease.

The pontomesencephalotegmental cholinergic system does not degenerate in Alzheimer's disease

The pedunculopontine and laterodorsal tegmental nuclei comprising the pontomesencephalotegmental (PMT) cholinergic system were examined for the presence of neuropathology and loss of presumed cholinergic cells in patients diagnosed with Alzheimer's disease-senile dementia of the Alzheimer type (AD-SDAT). Parkinsonian dementia, and multi-infarct dementia. Although neurofibrillary changes and plaque-like entities were observed in both nuclei in AD-SDAT and Parkinson's disease dementia, these pathologic indices were not seen consistently in control individuals or in those with multi-infarct dementia, and in none of the diagnostic categories was loss of neuronal somata found in the PMT cholinergic complex. Because appreciable degeneration of cholinergic neurons does occur in the basal forebrain in AD-SDAT, it is concluded that cholinergic phenotype alone is not a sufficient condition indicating predilection for neuronal loss in that dementing illness.

Cholinergic deficit in Alzheimer's disease: a study based on CSF and autopsy data.

Cholinesterase (ChE) activity was measured as a possible marker of cholinergic neurotransmission of the brain in CSF of 93 patients with probable Alzheimer's disease/senile dementia of the Alzheimer type (AD/SDAT) and of 29 control patients. ChE activity in CSF was decreased significantly in the AD/SDAT patients as compared to the controls. This reduction correlated significantly with the various measures of the severity of dementia. However, the reduction of ChE activity was only moderate (25-30%) even in patients with the most severe dementia and nonsignificant in patients with early symptoms of AD/SDAT. The significance of various confounding factors, which may interfere with CSF ChE measurements is discussed. Our findings seem to indicate that the deficiency of cholinergic neurons is not directly reflected in CSF and that the measurements of ChE activities in CSF are not helpful in diagnosing AD/SDAT. In the autopsy study the activities of cholineacetyltransferase (ChAT) and ChE were determined for ten brain areas of 20 AD/SDAT patients and of 14 controls. In AD/SDAT patients ChAT activity was profoundly decreased (50-85% decrease) in the cortical areas and hippocampus, but was unchanged or only mildly reduced in other subcortical brain areas. This study further confirms that the affection of cholinergic neurons is limited to projections from nucleus basalis to cortex and hippocampus, whereas other cholinergic neurons, like in striatum, seem to be relatively spared. In general, the activities of ChAT and ChE were lower in Alzheimer patients dying at younger age suggesting more severe disease process with these patients.

Chapter 21 The old animal as a model in research on brain aging and Alzheimer's disease/senile dementia of the Alzheimer type

Publisher Summary Limitations exist in employing rodents for studying Alzheimer's disease/senile dementia of the Alzheimer type (AD/SDAT), just as in studies on humans, and careful planning is, therefore, necessary. However, cross-sectional and/or longitudinal studies are more easily conducted in laboratory rodents because of their homogeneity, the possibility to rigorously control their environment, and their limited life span as compared to the larger laboratory animals—for example, monkeys, dogs, etc. Several aspects of husbandry and selection of mice and rats for research on aging in general are depicted in the chapter. A new approach, employing old rats for studying the possible effect of cholinergic deficits, is proposed in the chapter because old animals, when lesioned, might have less chance of regeneration and provide a better model for cholinergic changes in AD/SDAT. However, it should be stressed that several species should be employed for studying AD/SDAT and then the results obtained in each species may contribute to solve a part of the puzzle presently encountered in man.

Chapter 17 Neuronal cytoskeleton in aging and dementia

This chapter discusses the morphology and the biochemistry of neurofibrillary changes and their analogs in animal models. One of the cellular and molecular changes with aging is the formation of argentophilic intracellular neurofibrillary tangles in selected neurons of the aged human brain. These extraordinary neurofibrillary changes are seen in great abundance in several adult and late life dementias, especially the Alzheimer disease/senile dementia of the Alzheimer type (AD/SDAT). The Alzheimer neurofibrillary tangles (ANT) are composed of paired helical filaments (PHF). Bundles of these PHF are also found in the dystrophic neurites of the neuritic (senile) plaque, the second leading histopathological lesion of AD/SDAT. The normal neurofibrils are microtubules, neurofilaments, and microfilaments. The microtubules of the neuron are apparently identical to those in glial cells and all eukaryotic cells. PHF have, by sodium dodecyl sulfate polyacrylamide gel electrophoresis, a heterogeneous polypeptide composition, which might vary from 2–3 major bands in the 45 kDa–62 kDa area to a ladder of polypeptides with molecular weight difference of less than 5 kDa between the adjacent bands. This protein composition of isolated PHF is different from that of neurofilaments, microtubules, plaque amyloid, and scrapie-associated fibrils. Although a number of normal brain polypeptides have been shown to cross-react immunochemically with PHF, only the presence of microtubule-associated proteins, tau, in PHF has been demonstrated.

Alzheimer paired helical filaments: cross-reacting polypeptide/s normally present in brain.

Antisera to microtubule-enriched fraction from normal human brain (anti-MT sera) label neurofibrillary tangles and neurites of neuritic (senile) plaques in brain sections of cases with Alzheimer disease/senile dementia of the Alzheimer type (AD/SDAT); the plaque core amyloid is not labeled. These anti-MT sera label both tangles in tissue sections and smears of isolated tangles which had been extracted with sodium dodecyl sulfate (SDS) to remove impurities trapped in between the paired helical filaments (PHF). The tangle labeling of anti-MT sera is eliminated on their absorption both with microtubule-enriched fractions from human and animal brain and with the isolated PHF. Neurofilament triplet, actin, myosin, keratin, or fibroblasts do not absorb the tangles staining antibodies. Furthermore, antisera containing antibodies to tubulin, microtubule-associated high mol. wt. polypeptides (MAPS), neurofilament triplet, and the 50,000 mol. wt. contaminant of CNS neurofilament preparations do not label tangles. On immunoblots of SDS-polyacrylamide gels of isolated PHF anti-MT sera label some of the same polypeptides identified with antisera to PHF; affinity-purified antibodies to tubulin used as a control do not label any PHF polypeptide on the immunoblots. The anti-MT sera, when preabsorbed with the PHF polypeptides eluted from SDS-polyacrylamide gels, do not label tangles. These studies demonstrate that a polypeptide/s cross-reactive with Alzheimer PHF is indeed normally present in brain and that it is different from tubulin, neurofilament triplet, actin, myosin, vimentin, and keratin.

Alzheimer paired helical filaments: bulk isolation, solubility, and protein composition.

A method has been developed for the bulk isolation of Alzheimer neurofibrillary tangles (ANT) of paired helical filaments (PHF) from histopathologically confirmed cases of Alzheimer disease/senile dementia of the Alzheimer type (AD/SDAT). The fresh or frozen autopsied cerebral cortex affected with Alzheimer neurofibrillary changes is dissociated by homogenization and sieving through nylon bolting cloth and the ANT are separated by a combination of sucrose discontinuous density gradient centrifugation, glass bead column chromatography, and sodium dodecyl sulfate (SDS) treatment. The isolated ANT produce red-green birefringence when viewed through polarized light after staining with Congo red. Ultrastructurally, the isolated PHF are well preserved and have the dimensions of the PHF seen in situ. Two major Populations of ANT which exist in different proportions in AD/SDAT brains are identified on the basis of their solubility in SDS. The ANT I and the ANT II are soluble and insoluble respectively on treatment with 2% SDS at room temperature for 5 min. Solubilization of the ANT II requires several repeated extractions with a solution containing 10% each of SDS and beta-mercaptoethanol (BME) at 100 degrees C for 10 min. Sonication of the ANT II greatly facilitates their solubilization. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of the isolated ANT reveals the presence of two major polypeptides with molecular weights (MW) of 62,000 and 57,000, several minor polypeptides with MW below 57,000, and a significant amount of material not entering the stacking and the resolving gels. Re-electrophoresis of polypeptides extracted from various areas of the resolving gel or of the material which does not enter the gel generates the same polypeptide profile as on the first gel, suggesting that the PHF material which does not enter the gel may result from the reaggregation of the polypeptides that enter the resolving gel. None of the polypeptides that enter the resolving gel. None of the polpeptides observed in the isolated PHF comigrate in the SDS-PAGE with any of the neurofilament polypeptides, tubulin, actin, or myosin.