Alzheimer Disease: Shi Q

Gibson GE, Karuppagounder SS, Shi Q. · Department of Neurology and Neuroscience, Weill Medical College of Cornell University, Burke Medical Research Institute, White Plains, NY 10605, USA. · Ann N Y Acad Sci. · Pubmed #19076444 No free full text.

Abstract: Considerable data support the hypothesis that mitochondrial abnormalities link gene defects and/or environmental insults to the neurodegenerative process. The interaction of oxidants with calcium and the mitochondrial enzymes of the tricarboxylic acid cycle are central to that relationship. Abnormalities that were discovered in brains or fibroblasts from patients with Alzheimer's disease (AD) have been modeled in vitro and in vivo to assess their pathophysiological importance and to determine how they might be reversed. The conclusions are consistent with the hypothesis that the AD-related abnormalities result from oxidative stress. The selection of compounds for reversal is complex because the actions of the relevant compounds vary under different conditions, such as cell redox states and acute versus chronic changes. However, the models that have been developed are useful for testing the effectiveness of the potential medications. The results suggest that the reversal of mitochondrial deficits and a reduction in oxidative stress will reduce clinical and pathological changes and benefit patients.

Shi Q, Gibson GE. · Department of Neurology and Neuroscience, Weill Medical College of Cornell University, Burke Medical Research Institute, White Plains, NY 10605, USA. · Alzheimer Dis Assoc Disord. · Pubmed #18090434 No free full text.

Abstract: Alzheimer disease (AD) is defined by progressive impairments in memory and cognition and by the presence of extracellular neuritic plaques and intracellular neurofibrillary tangles. However, oxidative stress and impaired mitochondrial function always accompany AD. Mitochondria are a major site of production of free radicals [ie, reactive oxygen species (ROS)] and primary targets of ROS. ROS are cytotoxic, and evidence of ROS-induced damage to cell membranes, proteins, and DNA in AD is overwhelming. Nevertheless, therapies based on antioxidants have been disappointing. Thus, alternative strategies are necessary. ROS also act as signaling molecules including for transcription. Thus, chronic exposure to ROS in AD could activate cascades of genes. Although initially protective, prolonged activation may be damaging. Thus, therapeutic approaches based on modulation of these gene cascades may lead to effective therapies. Genes involved in several pathways including antioxidant defense, detoxification, inflammation, etc, are induced in response to oxidative stress and in AD. However, genes that are associated with energy metabolism, which is necessary for normal brain function, are mostly down-regulated. Redox-sensitive transcription factors such as activator protein-1, nuclear factor-kappaB, specificity protein-1, and hypoxia-inducible factor are important in redox-dependent gene regulation. Peroxisome proliferators-activated receptor-gamma coactivator (PGC-1alpha) is a coactivator of several transcription factors and is a potent stimulator of mitochondrial biogenesis and respiration. Down-regulated expression of PGC-1alpha has been implicated in Huntington disease and in several Huntington disease animal models. PGC-1alpha role in regulation of ROS metabolism makes it a potential candidate player between ROS, mitochondria, and neurodegenerative diseases. This review summarizes the current progress on how oxidative stress regulates the expression of genes that might contribute to AD pathophysiology and the implications of the transcriptional modifications for AD. Finally, potential therapeutic strategies based on the updated understandings of redox state-dependent gene regulation in AD are proposed to overcome the lack of efficacy of antioxidant therapies.

Shi Q, Hu X, Prior M, Yan R. · Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA. · J Neurosci. · Pubmed #19386906 No free full text.

Abstract: Reticulon 3 (RTN3) has been shown to mark a distinct and abundant population of dystrophic neurites named RTN3 immunoreactive dystrophic neurites (RIDNs) in patients' brains of Alzheimer disease (AD). Transgenic mice expressing RTN3 (Tg-RTN3) also spontaneously develop RIDNs. To determine whether RIDNs formed in Tg-RTN3 mice would ever naturally occur in the nontransgenic mouse brain, we targeted our examination to elderly mouse brains on the basis that AD is an age-dependent neurodegenerative disease where the decline in cognitive function becomes progressively increased during the course of the disease. Here, we demonstrate that the distribution of RIDNs is abundant, rather than sporadic, in elderly but not young mouse brains. RIDNs in the elderly brain have two distinct populations: abundantly dispersed RIDNs that can only be marked by RTN3, and less abundantly clustered RIDNs that can be marked by multiple proteins including RTN3, ubiquitin, and phosphorylated neurofilament. The abundance of RIDNs in Tg-RTN3 mice at the age of 3 months resembles that of 24-month-old wild type mice, suggesting that this animal model mimics and accelerates the natural occurrence of RIDNs. Importantly, we demonstrate that preformed RIDNs appear to reduce dendritic spine density and synaptic function. Further analysis from mechanistic studies suggests that elevated levels of RTN3 lead to an imbalance in the axonal transport of RTN3, which results in the accumulation of RTN3 in swollen neurites. Collectively, these results suggest that blocking the formation of RIDNs may be a promising strategy to impede cognitive decline in the elderly and in AD patients.

Shi Q, Xu H, Kleinman WA, Gibson GE. · Department of Neurology and Neuroscience, Weill Medical College of Cornell University/Burke Medical Research Institute, White Plains, New York 10605, USA. · Biochim Biophys Acta. · Pubmed #18206986 No free full text.

Abstract: Measures in autopsied brains from Alzheimer's Disease (AD) patients reveal a decrease in the activity of alpha-ketoglutarate dehydrogenase complex (KGDHC) and an increase in malate dehydrogenase (MDH) activity. The present experiments tested whether both changes could be caused by the common oxidant H(2)O(2) and to probe the mechanism underlying these changes. Since the response to H(2)O(2) is modified by the level of the E2k subunit of KGDHC, the interaction of MDH and KGDHC was studied in cells with varying levels of E2k. In cells with only 23% of normal E2k protein levels, one-hour treatment with H(2)O(2) decreased KGDHC and increased MDH activity as well as the mRNA level for both cytosolic and mitochondrial MDH. The increase in MDH did not occur in cells with 100% or 46% of normal E2k. Longer treatments with H(2)O(2) inhibited the activity of both enzymes. Glutathione is a major regulator of cellular redox state and can modify enzyme activities. H(2)O(2) converts reduced glutathione (GSH) to oxidized glutathione (GSSG), which reacts with protein thiols. Treatment of purified KGDHC with GSSG leads to glutathionylation of all three KGDHC subunits. Thus, cellular glutathione level was manipulated by two means to determine the effect on KGDHC and MDH activities. Both buthionine sulfoximine (BSO), which inhibits glutathione synthesis without altering redox state, and H(2)O(2) diminished glutathione to a similar level after 24 h. However, H(2)O(2), but not BSO, reduced KGDHC and MDH activities, and the reduction was greater in the E2k-23 line. These findings suggest that the E2k may mediate diverse responses of KGDHC and MDH to oxidants. In addition, the differential response of activities to BSO and H(2)O(2) together with the in vitro interaction of KGDHC with GSSG suggests that glutathionylation is one possible mechanism underlying oxidative stress-induced inhibition of the TCA cycle enzymes.

He W, Shi Q, Hu X, Yan R. · Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. · J Biol Chem. · Pubmed #17699523 links to  free full text

Abstract: Reticulon 3 (RTN3) has recently been shown to modulate Alzheimer BACE1 activity and to play a role in the formation of dystrophic neurites present in Alzheimer brains. Despite the functional importance of this protein in Alzheimer disease pathogenesis, the functional correlation to the structural domain of RTN3 remained unclear. RTN3 has two long transmembrane domains, but its membrane topology was not known. We report here that the first transmembrane domain dictates membrane integration and its membrane topology. RTN3 adopts a omega-shape structure with two ends facing the cytosolic side. Subtle changes in RTN3 membrane topology can disrupt its binding to BACE1 and its inhibitory effects on BACE1 activity. Thus, the determination of RTN3 membrane topology may provide an important structural basis for our understanding of its cellular functions.

Hu X, Shi Q, Zhou X, He W, Yi H, Yin X, Gearing M, Levey A, Yan R. · Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA. · EMBO J. · Pubmed #17476306 links to  free full text

Abstract: Dystrophic neurites are swollen dendrites or axons recognizable near amyloid plaques as a part of important pathological feature of Alzheimer's disease (AD). We report herein that reticulon 3 (RTN3) is accumulated in a distinct population of dystrophic neurites named as RTN3 immunoreactive dystrophic neurites (RIDNs). The occurrence of RIDNs is concomitant with the formation of high-molecular-weight RTN3 aggregates in brains of AD cases and mice expressing mutant APP. Ultrastructural analysis confirms accumulation of RTN3-containing aggregates in RIDNs. It appears that the protein level of RTN3 governs the formation of RIDNs because transgenic mice expressing RTN3 will develop RIDNs, initially in the hippocampal CA1 region, and later in other hippocampal and cortical regions. Importantly, we show that the presence of dystrophic neurites in Tg-RTN3 mice causes impairments in spatial learning and memory, as well as synaptic plasticity, implying that RIDNs potentially contribute to AD cognitive dysfunction. Together, we demonstrate that aggregation of RTN3 contributes to AD pathogenesis by inducing neuritic dystrophy. Inhibition of RTN3 aggregation is likely a therapeutic approach for reducing neuritic dystrophy.

Uc EY, Rizzo M, Anderson SW, Shi Q, Dawson JD. · Division of Neuroergonomics, Department of Neurology, College of Medicice, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA. · J Neurol Sci. · Pubmed #17049360 No free full text.

Abstract: Drivers with cognitive impairment are at increased odds for vehicular crashes. Rear-end collisions (REC) are among the most common crash types. We tested REC avoidance in 61 drivers with mild Alzheimer's disease (AD) and 115 elderly controls using a high-fidelity interactive driving simulator. After a segment of uneventful driving, each driver suddenly encountered a lead vehicle stopped at an intersection, creating the potential for a collision with lead vehicle or with another vehicle following closely behind the driver. Eighty-nine percent of drivers with AD had unsafe outcomes, either an REC or an risky avoidance behavior (defined as slowing down abruptly or prematurely, or swerving out of the traffic lane) compared to 65% of controls (P=0.0007). Crash rates were similar in AD (5%) and controls (3%), yet a greater proportion of drivers with AD slowed down abruptly (70% vs. 37%, P<0.0001) or prematurely (66% vs. 45%, P=0.0115). Abrupt slowing increased the odds of being struck from behind by the following vehicle (P=0.0262). Unsafe outcomes were predicted by tests of visual perception, attention, memory, visuospatial/constructional abilities, and executive functions, as well as vehicular control measures during an uneventful driving segment. Drivers with AD had difficulty responding to driving conditions that pose a hazard for a REC. Some cognitive and visual tests were predictive of unsafe outcomes even after adjusting for disease status.

He W, Hu X, Shi Q, Zhou X, Lu Y, Fisher C, Yan R. · Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. · J Mol Biol. · Pubmed #16979658 No free full text.

Abstract: BACE1 is a membrane-bound aspartyl protease that specifically cleaves amyloid precursor protein (APP) at the beta-secretase site. Membrane bound reticulon (RTN) family proteins interact with BACE1 and negatively modulate BACE1 activity through preventing access of BACE1 to its cellular APP substrate. Here, we focused our study on RTN3 and further show that a C-terminal QID triplet conserved among mammalian RTN members is required for the binding of RTN to BACE1. Although RTN3 can form homo- or heterodimers in cells, BACE1 mainly binds to the RTN monomer and disruption of the QID triplet does not interfere with the dimerization. Correspondingly, the C-terminal region of BACE1 is required for the binding of BACE1 to RTNs. Furthermore, we show that the negative modulation of BACE1 by RTN3 relies on the binding of RTN3 to BACE1. The knowledge from this study may potentially guide discovery of small molecules that can mimic the effect of RTN3 on the inhibition of BACE1 activity.

Uc EY, Rizzo M, Anderson SW, Shi Q, Dawson JD. · Department of Neurology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, USA. · J Neurol Neurosurg Psychiatry. · Pubmed #15897495 links to  free full text

Abstract: OBJECTIVE: To assess visual search and recognition of roadside targets and safety errors during a landmark and traffic sign identification task in drivers with Alzheimer's disease. METHODS: 33 drivers with probable Alzheimer's disease of mild severity and 137 neurologically normal older adults underwent a battery of visual and cognitive tests and were asked to report detection of specific landmarks and traffic signs along a segment of an experimental drive. RESULTS: The drivers with mild Alzheimer's disease identified significantly fewer landmarks and traffic signs and made more at-fault safety errors during the task than control subjects. Roadside target identification performance and safety errors were predicted by scores on standardised tests of visual and cognitive function. CONCLUSIONS: Drivers with Alzheimer's disease are impaired in a task of visual search and recognition of roadside targets; the demands of these targets on visual perception, attention, executive functions, and memory probably increase the cognitive load, worsening driving safety.

Uc EY, Rizzo M, Anderson SW, Shi Q, Dawson JD. · Division of Neuroergonomics, Department of Neurology, College of Medicine, University of Iowa, Iowa City, IA, USA. · Neurology. · Pubmed #15365132 No free full text.

Abstract: OBJECTIVE: To assess navigation and safety errors during a route-following task in drivers with Alzheimer disease (AD). DESIGN/METHODS: Thirty-two subjects with probable AD (by National Institute of Neurological and Communicative Disorders criteria) of mild severity and 136 neurologically normal older adults were tested on a battery of visual and cognitive tests of abilities that are critical to safe automobile driving. Each driver also performed a route-finding task administered on the road in an instrumented vehicle. Main outcome variables were number of 1) incorrect turns; 2) times lost; and 3) at-fault safety errors. RESULTS: The drivers with mild AD made significantly more incorrect turns, got lost more often, and made more at-fault safety errors than control subjects, although their basic vehicular control abilities were normal. The navigational and safety errors were predicted using scores on standardized tests sensitive to visual and cognitive decline in early AD. CONCLUSIONS: Drivers with Alzheimer disease made more errors than neurologically normal drivers on a route-following task that placed demands on driver memory, attention, and perception. The demands of following route directions probably increased the cognitive load during driving, which might explain the higher number of safety errors.

Gibson GE, Haroutunian V, Zhang H, Park LC, Shi Q, Lesser M, Mohs RC, Sheu RK, Blass JP. · Department of Neurology and Neuroscience, Weill Medical College of Cornell University, White Plains, NY 10605, USA. · Ann Neurol. · Pubmed #10976635 No free full text.

Abstract: Brain metabolism and the activity of the alpha-ketoglutarate dehydrogenase complex (KGDHC), a mitochondrial enzyme, are diminished in brains from patients with Alzheimer's disease (AD). In 109 subjects, the Clinical Dementia Rating (CDR) score was highly correlated with brain KGDHC activity. In AD patients who carried the epsilon 4 allele of the apolipoprotein E gene (ApoE4), the CDR score correlated better with KGDHC activity than with the densities of neuritic plaques or neuritic tangles. In contrast, in patients without ApoE4, the CDR score correlated significantly better with tangles and plaques than with KGDHC activity. The results suggest that mitochondrial/oxidative damage may be more important for the cognitive dysfunction in AD patients who carry ApoE4 than in those who do not.