Lonnie E. Schneider

Alzheimer's disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons

Alzheimers disease (AD) is associated with regional reductions in fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the cerebral metabolic rate for glucose, which may begin long before the onset of histopathological or clinical features, especially in carriers of a common AD susceptibility gene. Molecular evaluation of cells from metabolically affected brain regions could provide new information about the pathogenesis of AD and new targets at which to aim disease-slowing and prevention therapies. Data from a genome-wide transcriptomic study were used to compare the expression of 80 metabolically relevant nuclear genes from laser-capture microdissected non-tangle-bearing neurons from autopsy brains of AD cases and normal controls in posterior cingulate cortex, which is metabolically affected in the earliest stages; other brain regions metabolically affected in PET studies of AD or normal aging; and visual cortex, which is relatively spared. Compared with controls, AD cases had significantly lower expression of 70% of the nuclear genes encoding subunits of the mitochondrial electron transport chain in posterior cingulate cortex, 65% of those in the middle temporal gyrus, 61% of those in hippocampal CA1, 23% of those in entorhinal cortex, 16% of those in visual cortex, and 5% of those in the superior frontal gyrus. Western blots confirmed underexpression of those complex I–V subunits assessed at the protein level. Cerebral metabolic rate for glucose abnormalities in FDG PET studies of AD may be associated with reduced neuronal expression of nuclear genes encoding subunits of the mitochondrial electron transport chain.

Quantitative Cytochrome Oxidase Histochemistry: Applications in Human Alzheimer's Disease and Animal Models

Abstract Quantitative cytochrome oxidase (CO) histochemistry provides an intracellular measure of oxidative energy metabolic capacity that can be used as a tool to evaluate brain functional changes. CO enzyme activity also has been shown to be catalytically abnormal in patients with Alzheimers disease (AD). The application of CO histochemistry to postmortem AD and control human brains, as well as in comparative studies of murine models, is presented here, from the cellular to laminar to regional and multiregional levels of analysis. In AD cases and controls, we compared CO in 11 brain regions-of-interest (ROIs), including laminar analyses in seven neocortical regions. In a transgenic mouse model of AD and controls, we compared CO in 56 ROIs, providing information about both regional and network activity. Results highlight cellular and laminar vulnerabilities in AD and illustrate homologies between AD cases and a murine model of AD, with age-related reductions in CO activity within circuits implicated in spatial and discriminative learning. Quantitative CO histochemistry is a useful tool for the ex vivo assessment of functional changes within brain regions and neural networks, and its application has provided support for the hypothesis that mitochondrial dysfunction is involved in the pathophysiology of AD. (The J Histotechnol 30:235, 2007) Submitted September 11, 2007; accepted with modifications October 17, 2007