Faculty Bibliography

Amyloid protein deposited in cerebral vessel walls and diffuse plaques of patients with hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), is similar to the 40-42 residues amyloid beta (Abeta) in vessel walls and senile plaques in brains of patients with Alzheimer's disease (AD), Down's syndrome, and familial and sporadic cerebral amyloid angiopathy (CAA). In 1990 we sequenced the amyloid beta-protein precursor (AbetaPP) gene from HCHWA-D patients revealing a single mutation that results in an amino acid substitution, Abeta E22Q. Subsequent identification of additional mutations in the AbetaPP gene in familial AD (FAD) pedigrees revealed that whereas substitutions in the middle of Abeta, residues Abeta21-23, are predominantly vasculotropic, those found amino- or carboxyl-terminal to the Abeta sequence within AbetaPP enhance amyloid parenchymal plaque deposition. Studies of transfected cells showed that substitutions amino- or carboxyl-terminal to Abeta lead to either greater Abeta production or to enhanced secretion of the more hydrophobic thus more fibrillogenic Abeta1-42. Substitutions in the center of Abeta facilitate rapid aggregation and fibrillization, slower clearance across the blood-brain barrier and perivascular drainage to the systemic circulation, possibly higher resistance to proteolysis, and enhanced toxicity towards endothelial and smooth muscle cells. However, most AD patients have no genetic defects in AbetaPP, indicating that other factors may alter Abeta production, conformation, and/or clearance initiating the disease process

The ability to form tenable hypotheses regarding the neurobiological basis of normative functions as well as mechanisms underlying neurodegenerative and neuropsychiatric disorders is often limited by the highly complex brain circuitry and the cellular and molecular mosaics therein. The brain is an intricate structure with heterogeneous neuronal and nonneuronal cell populations dispersed throughout the central nervous system. Varied and diverse brain functions are mediated through gene expression, and ultimately protein expression, within these cell types and interconnected circuits. Large-scale high-throughput analysis of gene expression in brain regions and individual cell populations using modern functional genomics technologies has enabled the simultaneous quantitative assessment of dozens to hundreds to thousands of genes. Technical and experimental advances in the accession of tissues, RNA amplification technologies, and the refinement of downstream genetic methodologies including microarray analysis and real-time quantitative PCR have generated a wellspring of informative studies pertinent to understanding brain structure and function. In this review, we outline the advantages as well as some of the potential challenges of applying high throughput functional genomics technologies toward a better understanding of brain tissues and diseases using animal models as well as human postmortem tissues

In summary, NPY is clearly an important peptide in the adult rat dentate gyrus because it has the potential to influence synaptic transmission and neurogenesis. It may even have other functions, as yet undiscovered, mediated by glia or vasculature. The remarkable plasticity of NPY puts it in a position to allow dentate gyrus function to be modified in a changing environment. The importance of this plasticity in the context of epilepsy cannot be emphasized enough. It could help explain a range of observations about epilepsy that currently is poorly understood. For example, rapid increases in NPY could mediate postictal depression, the period of depression that can last for several hours after generalized seizures. It may mediate the 'priming effect,' which is a reduction in seizure threshold following an initial period of seizures. Finally, it could contribute to the resistance of dentate granule cells to degeneration after seizures. However, despite the focus in this review on seizure-induced changes, the changes described here also appear to occur after other types of manipulations, which considerably broadens the scope of NPY's role in the brain

Intracellular management of cholesterol is a critical process in the brain. Deficits with cholesterol transport and storage are linked to neurodegenerative disorders such as Neimann-Pick disease type C and Alzheimer's disease. One protein putatively involved in cholesterol transport is metastatic lymph node 64 (MLN64). MLN64 localizes to late endosomes which are part of the cholesterol internalization pathway. However, a detailed pattern of MLN64 expression in the brain is unclear. Using immunocytochemical and immunoblot analyses, we demonstrated the presence of MLN64 in several tissue types and various regions within the brain. MLN64 immunostaining in the CNS was heterogeneous, indicating selective expression in discrete specific cell populations and regions. MLN64 immunoreactivity was detected in glia and neurons, which displayed intracellular labeling consistent with an endosomal localization. Although previous studies suggested that MLN64 may promote steroid production in the brain, MLN64 immunoreactivity did not colocalize with steroidogenic cells in the CNS. These results demonstrate that MLN64 is produced in the mouse and human CNS in a restricted pattern of expression, suggesting that MLN64 serves a cell-specific function in cholesterol transport.