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PubMed2001

A quantitative assessment of glycolipid and protein associated with paired helical filament preparations from Alzheimer's diseased brain.

Protease resistant paired helical filaments (prcPHF) can be isolated from the brains of Alzheimer's diseased patients. A second type of PHF, A68 PHF, may be extracted in soluble form from brain homogenate and induced to form filaments in vitro. Here we use a variety of analytical techniques to assess the protein, carbohydrate and fatty acid composition of prcPHF and A68 PHF. High-field ^1H NMR of both PHF preparations display similar fatty acid and carbohydrate proton resonances, consistent with the presence of a structurally similar glycolipid. Carbohydrate analysis showed that both preparations contained greater than 82% less than 12% C16:1 was significantly lower in A68 PHF than in prcPHF, both preparations contained otherwise similar fatty acid profiles with the most abundant lipid component being oleic acid (C18:1, 29.3 +/- 9.0%) followed by palmitic (C16:0, 28.5 +/- 5.6%) 17.6 +/- 7.5%) preparations revealed a profile reasonably consistent with that previously determined for PHF-tau but significantly higher in glycine and lower in lysine than would be predicted from the cDNA sequence. On a weight per cent basis, protein accounted for about 51% A68 PHF samples but only about 10% Carbohydrate and fatty acid accounted for about 39% A68 PHF samples but 74% preparations showed strong correlations between the total amount of tau protein and fatty acid. These results suggest that a glycolipid component forms an integral part of the PHF structure.

Journal Article↗
PubMedDate not supplied

Impaired phosphoinositide hydrolysis in Alzheimer's disease brain.

The effect of Alzheimer's disease (AD) on the activity of the phosphoinositide second messenger system was studied by measuring the hydrolysis of [3H]phosphatidylinositol (PI) by membranes from postmortem human prefrontal cortex. The activity of phospholipase C was similar in AD and control tissue. Activation with GTP gamma S and with carbachol demonstrated less [3H]PI hydrolysis in AD than control membranes. The concentration of Gq/11, the G-proteins most likely functional in phosphoinositide metabolism, was unchanged in AD compared with controls, indicating that function of the receptor-G-protein complex rather than the G-protein concentration was the site of the impairment in AD. These results indicate that postsynaptic muscarinic receptor responses are impaired in AD, a finding that may explain, in part, the limited therapeutic responses achieved by administration of cholinomimetics to patients with AD. Also, this assay provides a means to identify cholinomimetics that are most effective in activating muscarinic receptor-coupled phosphoinositide hydrolysis in human brain, agents which should have the greatest potential for providing therapeutic responses in AD.

Aged↗
PubMed2004

Mapping cortical change in Alzheimer's disease, brain development, and schizophrenia.

This paper describes algorithms that can identify patterns of brain structure and function associated with Alzheimer's disease, schizophrenia, normal aging, and abnormal brain development based on imaging data collected in large human populations. Extraordinary information can be discovered with these techniques: dynamic brain maps reveal how the brain grows in childhood, how it changes in disease, and how it responds to medication. Genetic brain maps can reveal genetic influences on brain structure, shedding light on the nature-nurture debate, and the mechanisms underlying inherited neurobehavioral disorders. Recently, we created time-lapse movies of brain structure for a variety of diseases. These identify complex, shifting patterns of brain structural deficits, revealing where, and at what rate, the path of brain deterioration in illness deviates from normal. Statistical criteria can then identify situations in which these changes are abnormally accelerated, or when medication or other interventions slow them. In this paper, we focus on describing our approaches to map structural changes in the cortex. These methods have already been used to reveal the profile of brain anomalies in studies of dementia, epilepsy, depression, childhood- and adult-onset schizophrenia, bipolar disorder, attention-deficit/hyperactivity disorder, fetal alcohol syndrome, Tourette syndrome, Williams syndrome, and in methamphetamine abusers. Specifically, we describe an image analysis pipeline known as cortical pattern matching that helps compare and pool cortical data over time and across subjects. Statistics are then defined to identify brain structural differences between groups, including localized alterations in cortical thickness, gray matter density (GMD), and asymmetries in cortical organization. Subtle features, not seen in individual brain scans, often emerge when population-based brain data are averaged in this way. Illustrative examples are presented to show the profound effects of development and various diseases on the human cortex. Dynamically spreading waves of gray matter loss are tracked in dementia and schizophrenia, and these sequences are related to normally occurring changes in healthy subjects of various ages.

Algorithms↗