Normal cortical concentration of cholecystokinin-like immunoreactivity with reduced choline acetyltransferase activity in senile dementia of Alzheimer type

Choline acetyltransferase (ChAT) activity and cholecystokinin immunoreactivity (CCK-I) were determined in ten brains from patients dying with a diagnosis of senile dementia of Alzheimer type (SDAT) and in ten brains from control cases. The post-mortem stability of CCK-I was high, as determined using a mouse brain model. Although ChAT activity was significantly reduced in the cerebral cortex, hippocampus and caudate nucleus in the SDAT cases, there was no difference in CCK-I content between the two groups in any brain area. Thus the population of intrinsic cortical cells which contains CCK-I does not appear to be significantly affected in SDAT.     

Is Alzheimer's senile dementia associated with the phenomena of reactive synaptogenesis in the hippocampus?

The densities of specific binding sites for glutamate or its analogue kainate were determined in the hippocampi of patients having suffered of senile dementia of the Alzheimer type (SDAT) and compared to age matched controls. The densities of sites were reduced in SDAT cases. These results indicate a lack of hippocampal plasticity in senile dementia of Alzheimer type.     

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.     

Quantitative analysis of the distribution of acetylcholinesterase-positive senile plaques in the hippocampal formation in patients with senile dementia of Alzheimer type

Senile plaques (SP) are one of the major neuropathologic hallmarks of senile dementia of Alzheimer type (SDAT). The regional distribution of SP stained for acetylcholinesterase (AChE) has been quantified in the hippocampal formation of patients with SDAT. Consistent differences in plaque distribution and density were observed between different patients. SP were significantly more numerous in the outer dentate molecular layer, whereas their density was low in other hippocampal regions. The quantity of AChE positive SP seemed to correlate with the density of neurofibrillary tangles in the entorhinal cortex. The AChE positive SP had a pattern of distribution different from the one observed with Thioflavin S. These results are discussed in light of a possible sprouting of cholinergic septal afferents.     

Recent cerebrospinal fluid biomarker studies of Alzheimer’s disease

Alzheimer’s disease is a progressive neurodegenerative disorder and the most common form of dementia. The disease is confirmed by the presence of neuritic plaques and neurofibrillary tangles in the cerebral cortex at autopsy, but the accuracy of antemortem diagnosis, especially at the early stages of the disease, is not ideal. Thus, there is a substantial need for the discovery and validation of diagnostic biomarkers. Many Alzheimer’s disease biomarker discovery studies emphasize the analysis of cerebrospinal fluid (CSF) because of its close association with the brain. Here, we review recent mass spectrometry-based studies of Alzheimer’s disease CSF, and additionally discuss issues associated with CSF in proteomics studies.     

Decreased level of beta-endorphin-like immunoreactivity in cerebrospinal fluid of patients with senile dementia of Alzheimer type

beta-Endorphin-like immunoreactivity in cerebrospinal fluid(CSF) was observed to decrease in patients with Huntington's disease and dementia due to brain vascular disease. The greatest decrease was seen in patients with presenile and senile dementia of Alzheimer type(SDAT). The immunoreactivity significantly correlated with psychological functions when examined using a dementia rating scale (r=0.51, p less than 0.01, for all dementia, r=0.65, p less than 0.02, for only SDAT). These results suggest that a B-endorphin-like substance may be related in the pathophysiology of dementia.     

Targeting alzheimer amyloid plaques in vivo

The only definitive diagnosis for Alzheimer disease (AD) at present is postmortem observation of neuritic plaques and neurofibrillary tangles in brain sections. Radiolabeled amyloid-beta peptide (Abeta), which has been shown to label neuritic plaques in vitro, therefore could provide a diagnostic tool if it also labels neuritic plaques in vivo following intravenous injection. In this study, we show that the permeability of Abeta at the blood-brain barrier can be increased by at least twofold through covalent modification with the naturally occurring polyamine, putrescine. We also show that, following intravenous injection, radiolabeled, putrescine-modified Abeta labels amyloid deposits in vivo in a transgenic mouse model of AD, as well as in vitro in human AD brain sections. This technology, when applied to humans, may be used to detect plaques in vivo, allowing early diagnosis of the disease and therapeutic intervention before cognitive decline occurs.     

Role of microglia in plaque formation in senile dementia of the Alzheimer type. An immunohistochemical study

Using immunohistochemical and enzyme histochemical methods, we have investigated the presence of mononuclear phagocytic cells around senile plaques in six brains from patients with senile dementia of the Alzheimer type (SDAT). It is generally supposed that reactive microglial cells are involved in amyloid formation "as representatives of the reticuloendothelial system in the brain." We used different monoclonal antibodies directed against cells of the mononuclear phagocyte lineage, antibodies against the macrophage markers alpha 1-antichymotrypsin and lysozyme, and the lectin WGA, in addition to enzyme histochemical staining for nonspecific esterase and acid phosphatase. It was concluded that no macrophages of the mononuclear phagocyte lineage are involved in plaque formation. The role of glial cells in amyloid formation is discussed.     

A familial case of Alzheimer's disease without tau pathology may be linked with chromosome 3 markers

Alzheimer's disease is the most common form of dementia that occurs in later years. The diagnosis is confirmed by the pathological findings of βA4-amyloid-containing neuritic plaques and neurofibrillary tangles, the former being present in sufficient quantity commensurate with age. Other forms of dementia are more difficult to diagnose clinically; their pathology is noted for the lack of plaques and tangles. A patient with a family history of dementia presented with the clinical signs of Alzheimer's disease which lasted for 13 years. At autopsy the brain tissue had βA4-amyloid-containing neuritic plaques, but no neurofibrillary tangles (i.e., the tissue was negative for staining with the tau antibody). Genetic analysis of DNA from family members revealed no linkage with chromosome 17 markers, indicating that this was not frontotemporal dementia. However, there was linkage with chromosome 3 markers. Thus, this form of Alzheimer's disease with a pathology of plaques only is linked with markers on chromosome 3. Electronic Publication     

Cortical Substance P-Like Immunoreactivity in Cases of Alzheimer's Disease and Senile Dementia of the Alzheimer Type

Abstract: The concentration of substance P-like immunoreactive material (SPLI) and somatostatin-like immunoreactive material (SLI) and the activity of acetyl-CoA: choline- O -acetyltransferase (ChAT; EC 2.3.1.6.) were measured in eight brain regions of 13 normal patients and 12 patients with Alzheimer disease/senile dementia of the Alzheimer type (AD/SDAT). SPLI was significantly lower in five of eight regions in the patients with AD/SDAT. Younger patients with AD/SDAT had significantly lower SLI in the parietal cortex than older patients. ChAT activity and SPLI in the parietal cortex of the presenile patients with ADISDAT were not significantly different from values found in older patients.     

125I-Galanin Binding Sites in Alzheimer's Disease: Increases in Hippocampal Subfields and a Decrease in the Caudate Nucleus

Abstract: Using iodinated human galanin and autoradiography, galanin binding sites were studied in cortical and hippocampal areas and in some brainstem nuclei in the brains of eight patients with senile dementia of the Alzheimer type (SDAT) and of nine matched control cases. The highest density of binding sites was found in the substantia nigra with a less intense labeling in the hippocampus and cortical regions. In the SDAT cases a significant increase in number of galanin binding sites was found in some hippocampal areas, a decrease in the caudate nucleus, and no significant changes in frontal and entorhinal cortices. These findings suggest that some central galanin systems may be deranged in SDAT.     

Staining Senile Plaques using Bodian's Method Modified with Methenamine

A new method is presented for staining various types of senile plaques isolated from the brains of patients with Alzheimer type dementia and related diseases in paraffin embedded sections using a modified Bodian's method with methenamine. This methenamine-Bodian method made it possible to observe diffuse plaques and other amyloid deposits which are barely detected by Bodian's original method. The staining of senile plaques by the method presented here was comparable to that of immunostaining with anti-β-protein. The new method also stained neurofibrillary tangles. Therefore, the methenamine-Bodian method could be widely used for the detection of senile changes in paraffin embedded sections from autopsied human brains.     

Cerebrospinal fluid and plasma corticotropin-releasing hormone in senile dementia.

Cerebrospinal fluid (CSF) levels of corticotropin-releasing hormone (CRH) and ACTH, and plasma levels of CRH, ACTH and cortisol were determined in samples taken simultaneously from 28 patients with dementia including senile dementia of the Alzheimer type (SDAT), multi-infarct dementia (MID), dementia following a cerebrovascular accident (CVD), and the borderline-to-normal state. CRH levels in CSF were significantly reduced in patients with SDAT and CVD, but not in those with MID, as compared with the borderline cases. ACTH levels in CSF were significantly reduced in the patients with SDAT compared to those with MID. Reduced CRH levels in CSF were found in the patients who showed severe dementia and poor activities of daily living (ADL). Plasma levels of CRH, ACTH and cortisol were normal and were not significantly different among the four groups of patients. CRH levels in CSF were positively correlated with ACTH levels in CSF, but not with the levels of plasma CRH, ACTH or cortisol. Plasma CRH levels were positively correlated with plasma ACTH levels. These results suggest that: 1) abnormalities in the extrahypothalamic CRH system play a role in the pathophysiology of senile dementia, which may not be specific to SDAT; 2) CSF CRH is correlated with the severity of dementia and ADL; 3) the levels of CRH in CSF and plasma are independent, and 4) the plasma CRH reflects, at least in part, the activity of the hypothalamic CRH regulating the secretion of pituitary ACTH.     

Heart Rate Variation, Age, and Behavior in Subjects with Senile Dementia of Alzheimer Type

Minute-by-minute heart rate (HR) recordings over a period of 24 h were obtained once for 30 elderly subjects diagnosed as having senile dementia of Alzheimer type (SDAT). Twenty-one of the subjects were studied in a hospital ward setting, and nine were studied in their own homes. Twelve were men and 18 were women. Eleven took some form of sedative medication; 10 took no medication. Thirty-minute mean values were unmasked to take account of the effects of activity and sleep on HR. Results indicate that the masked HR circadian rhythm of SDAT may be more often unimodal than that of normal subjects of similar age, and that phase shift of the endogenous, clock-mediated component of the rhythm (with higher HR at night) is to be expected in a proportion of individuals with SDAT.     

Tyrosine Hydroxylase, Tryptophan Hydroxylase, Biopterin, and Neopterin in the Brains of Normal Controls and Patients with Senile Dementia of Alzheimer Type

The activities of tyrosine hydroxylase and tryptophan hydroxylase, and the concentrations of the biopterin cofactor and the precursor neopterin were measured in 14 regions of postmortem brains from four histologically verified patients of senile dementia of the Alzheimer type (SDAT) and eight histologically normal controls. Neopterin concentrations were measured in the human brain for the first time. The activities of tyrosine hydroxylase and tryptophan hydroxylase in the brains of patients with SDAT were significantly reduced in the substantia nigra and in the lateral segment of the globus pallidus, locus ceruleus, and substantia nigra, respectively. The concentrations of total biopterin in the brains of patients with SDAT were significantly reduced in the putamen and substantia nigra, but the total neopterin concentrations did not change significantly. These results suggest that the reduction in biogenic amines in SDAT might be related to reductions in biosynthetic enzymes associated with biogenic amines, due to destruction of monoaminergic neurons.     

Detection of Neuritic Plaques in Alzheimer's Disease Mouse Model

Alzheimer''s disease (AD) is the most common neurodegenerative disorder leading to dementia. Neuritic plaque formation is one of the pathological hallmarks of Alzheimer''s disease. The central component of neuritic plaques is a small filamentous protein called amyloid β protein (Aβ)¹, which is derived from sequential proteolytic cleavage of the beta-amyloid precursor protein (APP) by β-secretase and γ-secretase. The amyloid hypothesis entails that Aγ-containing plaques as the underlying toxic mechanism in AD pathology². The postmortem analysis of the presence of neuritic plaque confirms the diagnosis of AD. To further our understanding of Aγ neurobiology in AD pathogenesis, various mouse strains expressing AD-related mutations in the human APP genes were generated. Depending on the severity of the disease, these mice will develop neuritic plaques at different ages. These mice serve as invaluable tools for studying the pathogenesis and drug development that could affect the APP processing pathway and neuritic plaque formation. In this protocol, we employ an immunohistochemical method for specific detection of neuritic plaques in AD model mice. We will specifically discuss the preparation from extracting the half brain, paraformaldehyde fixation, cryosectioning, and two methods to detect neurotic plaques in AD transgenic mice: immunohistochemical detection using the ABC and DAB method and fluorescent detection using thiofalvin S staining method.     

Neuropeptide Y-like immunoreactivity in neuritic plaques of Alzheimer's disease

Alzheimer's disease, a form of senile dementia, is characterized by the presence of neuritic plaques and neurofibrillary tangles throughout the cortex and hippocampus. This study demonstrates the presence of neuropeptide Y-like immunoreactivity within 10-20% of neuritic plaques. Neuropeptide Y is a 36 amino acid peptide which is distributed unevenly throughout the brain and has an interneuronal location.     

Dermatoglyphic patterns in senile dementia of Alzheimer's type

Several reports suggest a genetic relationship between senile dementia of Alzheimer type (SDAT) and Down's syndrome. We have analyzed fingerprints and palmar patterns in an elderly female population comprising a group of 34 patients with probable SDAT, a group of 20 patients with other dementias, and a group of 20 non-demented controls. A bilateral Sydney line was found to be significantly more frequent in the SDAT group than in the two other groups (p less than 0.01, sensitivity 30%, specificity 95%, positive predictive value 91%, negative predictive value 61%). A bilateral Sydney line was as frequent in the SDAT group as in Down's syndrome. The limit value of the index of transversality equal or superior to 31, which is considered as a feature of Down's syndrome, was significantly more frequent in the SDAT group than in the two other groups (right hand p less than 0.05, left hand p less than 0.02). A bilateral discriminant value of this index was also significantly more frequent in the SDAT group than in the two other groups (p less than 0.02), as was an index of transversality higher than 31 on at least one hand (p less than 0.01). In contrast with other reports, we haven't found significantly different frequencies of digital ulnar loops and true hypothenar patterns between the SDAT group and the two others.     

Effects of Modeling of Hypercalcemia and β-Amyloid on Cultured Hippocampal Neurons of Rats

Neurophysiology - Alzheimer’s disease (AD) is the most common type of dementia; it is characterized by accumulations of amyloid (Aβ) plaques and neurofibrillary tangles in the brain....     

Targets of caspase-6 activity in human neurons and Alzheimer disease

Caspase-6 activation occurs early in Alzheimer disease and sometimes precedes the clinical manifestation of the disease in aged individuals. The active Caspase-6 is localized in neuritic plaques, in neuropil threads, and in neurofibrillary tangles containing neurons that are not morphologically apoptotic in nature. To investigate the potential consequences of the activation of Caspase-6 in neurons, we conducted a proteomics analysis of Caspase-6-mediated cleavage of human neuronal proteins. Proteins from the cytosolic and membrane subcellular compartments were treated with recombinant active Caspase-6 and compared with undigested proteins by two-dimensional gel electrophoresis. LC/MS/MS analyses of the proteins that were cleaved identified 24 different potential protein substrates. Of these, 40% were cytoskeleton or cytoskeleton-associated proteins. We focused on the cytoskeleton proteins because these are critical for neuronal structure and function. Caspase-6 cleavage of alpha-Tubulin, alpha-Actinin-4, Spinophilin, and Drebrin was confirmed. At least one Caspase-6 cleavage site was identified for Drebrin, Spinophilin, and alpha-Tubulin. A neoepitope antiserum to alpha-Tubulin cleaved by Caspase-6 immunostained neurons, neurofibrillary tangles, neuropil threads, and neuritic plaques in Alzheimer disease and co-localized with active Caspase-6. These results imply that the early and neuritic activation of Caspase-6 in Alzheimer disease could disrupt the cytoskeleton network of neurons, resulting in impaired neuronal structure and function in the absence of cell death. This study provides novel insights into the pathophysiology of Alzheimer disease.