Alzheimer Disease: Shie FS

Shie FS, Nivison M, Hsu PC, Montine TJ. · Division of Mental Health and Substance Abuse Research, National Health Research Institutes, No.35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, R.O.C. · Curr Med Chem. · Pubmed #19199928 No free full text.

Abstract: Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Although the etiology of AD remains unclear, microglia-mediated neuroinflammation is believed to play an important role in its pathogenesis. Microglial activation occurs in AD and is characterized by apparent phagocytic activity and by increased production and secretion of several cytokines, chemokines, reactive oxygen and nitrogen species, prostaglandin (PG)E2, and neurotrophic factors. Microglial activation can be neuroprotective through the release of neurotrophic factors and by phagocytosing Abeta, a critical neurotoxic component in AD brain. Concurrently, microglial activation causes elevated inflammatory responses that lead to paracrine damage to neurons. Therefore, a well-controlled microglial activation that diminishes microglial-mediated oxidative damage while promoting neuronal protection may be the key for AD therapy. Peroxisome proliferator-activated receptor gamma (PPARgamma) has recently gained increasing attention in AD due to its function as a molecular target for non-steroidal anti-inflammatory drugs (NSAIDs). In this review, we will discuss the role of PPARgamma in microglial innate immunity in AD and how pharmacological manipulation of microglial activation using PPARgamma ligands might facilitate the treatment of AD.

Shie FS, Woltjer RL. · Division of Mental Health and Substance Abuse, National Health Research Institutes, No.35 Keyan Road, Zhunan Town, Miaoli County 350, ROC, Taiwan. · Curr Med Chem. · Pubmed #18045132 No free full text.

Abstract: Alzheimer's disease (AD) is the leading cause of dementia. Although the etiology of AD remains controversial, the amyloid hypothesis suggests that beta-amyloid (Abeta) peptides may contribute to brain dysfunction, and microglial activation has become increasingly regarded as a potential contributor to disease pathogenesis. Microglial activation is characterized by morphological changes and by production of various effectors, and activated neuroinflammation concurrent with increased oxidative stress may contribute to damage to neurons. However, recently there has been a recognition that microglia may also play a neuroprotective role through their release of neurotrophic factors and through phagocytosis of Abeta. Thus, there is growing consensus that a favorable combination of diminished microglia-mediated neuroinflammation and enhanced Abeta clearance may be critical in AD therapy. In this review, we will discuss the role of microglial activation in AD and how pharmacologic manipulation of microglia might bear upon the treatment of AD.

Shie FS, Montine KS, Breyer RM, Montine TJ. · Department of Pathology, University of Washington, Seattle 98104, USA. · Brain Pathol. · Pubmed #15912885 No free full text.

Abstract: Epidemiologic and animal model data support a role for the prostaglandin pathway in AD pathogenesis. However, unexpected toxicity from protracted use of some nonsteroidal anti-inflammatory drugs (NSAIDs) compels investigation of therapeutic targets in this pathway other than COX inhibitors. Previously, we have shown that mice lacking one specific receptor for PGE2, EP2 (EP2-/-), are protected from the indirect neurotoxic effects of cerebral innate immune response mediated by CD14-dependent activation. Here we review data showing that EP2-/- microglia have a highly desirable combination of features: ablated indirect neurotoxicity following exposure to Abeta(1-42) coupled with enhanced phagocytosis of Abeta peptides, both synthetic and those deposited in human brain. These data point to microglial EP2 as a more focused target within the PG pathway for therapy in AD.

Brich J, Shie FS, Howell BW, Li R, Tus K, Wakeland EK, Jin LW, Mumby M, Churchill G, Herz J, Cooper JA. · Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. · J Neurosci. · Pubmed #12514215 links to  free full text

Abstract: The axonal microtubule stabilizing protein tau is hyperphosphorylated in several neurodegenerative conditions, including Alzheimer's disease, yet the genes that regulate tau phosphorylation are largely unknown. Disabled-1 (Dab1) is a cytoplasmic adapter protein that interacts with apolipoprotein E (ApoE) receptors and controls neuronal positioning during embryonic brain development. We have investigated the role of Dab1 in tau phosphorylation. We found that wild-type Dab1, but not a mutant lacking tyrosine phosphorylation sites, protects mice from the hyperphosphorylation of tau. However, the absence of Dab1 is not sufficient to cause tau hyperphosphorylation, because hyperphosphorylation is manifested only when Dab1 is mutated in specific mouse strain backgrounds. Tau hyperphosphorylation correlates with early death in susceptible mouse strains, and it occurs in the neurons of the hippocampus and dentate gyrus. By quantitative trait locus (QTL) analysis of Dab1-deficient mice on a hybrid strain background, we uncovered one significant and three suggestive chromosomal loci that modulate tau phosphorylation. Two of these QTL regions contain genes that are defective in early onset Alzheimer's disease. Our findings suggest that Dab1 gene disruption sensitizes mice to tau hyperphosphorylation contingent on specific haplotypes that are linked to Alzheimer's disease loci. Dab1 mutant mice provide an animal model for studying the relationships between ApoE receptors, tau hyperphosphorylation, and Alzheimer's disease.

Jin LW, Hua DH, Shie FS, Maezawa I, Sopher B, Martin GM. · Department of Pathology, University of Washington, Seattle 98195-7470, USA. · J Mol Neurosci. · Pubmed #12212794 No free full text.

Abstract: Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the progressive and global loss of cognitive functions. Pathological features include a loss of neurons in vulnerable brain regions and the extracellular deposition of abnormal protein aggregates known as amyloid plaques. Amyloid-beta protein (A beta is the major component of amyloid plaques and is derived from a larger transmembrane glycoprotein, termed amyloid beta protein precursor (APP), by proteolysis. The AD research has focused on A beta production and metabolism, its extracellular deposition, and its cellular toxicity. Recent evidence, however, suggests that A beta as well as the C-terminal fragments (CTF) of APP can accumulate intraneuronally. The neuronal loss and synaptic transmission deficit in AD may therefore depend on intraneuronal accumulation of A beta/CTF rather than on extracellular plaque formation. Accordingly, we propose that one of the primary targets of therapeutic intervention should be intracellular A beta/CTF and its toxic cellular effect. We have established a cell-culture model in which the neurons degenerate on induction of endogenous expression of A beta/CTF of APP. These cultures have been used to test whether tricyclic pyrone (TP) compounds may prevent A beta/CTF-mediated neuronal death. The results to date have been encouraging. Lead compounds will now be selected for their abilities to ameliorate A beta/CTF-mediated pathology in transgenic mice. Our hope is that these compounds may eventually prove beneficial for the prevention and treatment of AD.

Shie FS, Jin LW, Cook DG, Leverenz JB, LeBoeuf RC. · Nutritional Sciences Interdisciplinary Program and Department of Pathology, Box 353410, Raitt Hall, Room 305, University of Washington, Seattle, WA 98195, USA. · Neuroreport. · Pubmed #11930160 No free full text.

Abstract: Epidemiological data show correlations between hypercholesterolemia and Alzheimer's disease (AD). We test the hypothesis that hypercholesterolemia modulates Abeta deposition in mice overexpressing the human APP695 Swedish mutation (K670N and M671L) (TgAPPsw). Feeding mice a high fat/high cholesterol (HFHC) diet for 7-10 months increased total cholesterol levels by 4-fold. The extent of Abeta immunostained plaque-like deposits were significantly higher for mice fed the HFHC diet as compared with mice fed rodent chow. Extent of deposits correlated inversely with plasma levels of HDL and directly to apolipoprotein E. Overall, plasma lipoproteins may be an important factor in induction of AD-like plaques in mice. The lowering of plasma lipids may be therapeutic for AD patients.