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1.  Slc25a12 disruption alters myelination and neurofilaments: A model for a hypomyelination syndrome and childhood neurodevelopmental disorders 
Biological psychiatry  2009;67(9):887-894.
Background
SLC25A12, a susceptibility gene for autism spectrum disorders (ASDs) that is mutated in a neurodevelopmental syndrome, encodes a mitochondrial aspartate/glutamate carrier (AGC1). AGC1 is an important component of the malate/aspartate shuttle, a crucial system supporting oxidative phosphorylation and ATP production.
Methods
We characterized mice with a disruption of the Slc25a12 gene, followed by confirmatory in vitro studies.
Results
Slc25a12-knockout mice, which showed no AGC1 by immunoblotting, were born normally but displayed delayed development and died around 3 weeks after birth. In P13-14 knockout brains, the brains were smaller with no obvious alteration in gross structure. However, we found a reduction in myelin basic protein (MBP)-positive fibers, consistent with a previous report. Furthermore, the neocortex of knockout mice contained abnormal neurofilamentous accumulations in neurons, suggesting defective axonal transport and/or neurodegeneration. Slice cultures prepared from knockout mice also showed a myelination defect, and reduction of Slc25a12 in rat primary oligodendrocytes led to a cellautonomous reduction in MBP expression. Myelin deficits in slice cultures from knockout mice could be reversed by administration of pyruvate, indicating that reduction in AGC1 activity leads to reduced production of aspartate/N-acetyl aspartate (NAA) and/or alterations in the NADH/NAD+ ratio, resulting in myelin defects.
Conclusions
Our data implicate AGC1 activity in myelination and in neuronal structure, and indicate that while loss of AGC1 leads to hypomyelination and neuronal changes, subtle alterations in AGC1 expression could affect brain development contributing to increased autism susceptibility.
doi:10.1016/j.biopsych.2009.08.042
PMCID: PMC4067545  PMID: 20015484
Malate/aspartate shuttle; mitochondria; N-acetyl aspartate (NAA); neuron-oligodendrocyte interactions; pyruvate
2.  Neuropathology of the posteroinferior occipitotemporal gyrus in children with autism 
Molecular Autism  2014;5:17.
Background
While most neuropathologic studies focus on regions involved in behavioral abnormalities in autism, it is also important to identify whether areas that appear functionally normal are devoid of pathologic alterations. In this study we analyzed the posteroinferior occipitotemporal gyrus, an extrastriate area not considered to be affected in autism. This area borders the fusiform gyrus, which is known to exhibit functional and cellular abnormalities in autism.
Findings
No studies have implicated posteroinferior occipitotemporal gyrus dysfunction in autism, leading us to hypothesize that neuropathology would not occur in this area. We indeed observed no significant differences in pyramidal neuron number or size in layers III, V, and VI in seven pairs of autism and controls.
Conclusions
These findings are consistent with the hypothesis that neuropathology is unique to areas involved in stereotypies and social and emotional behaviors, and support the specificity of the localization of pathology in the fusiform gyrus.
doi:10.1186/2040-2392-5-17
PMCID: PMC3938306  PMID: 24564936
Autism; Fusiform gyrus; Neuropathology; Posteroinferior occipitotemporal gyrus; Stereology
3.  Association of ApoE and LRP mRNA levels with dementia and AD neuropathology 
Neurobiology of Aging  2011;33(3):628.e1-628.e14.
Inheritance of the ε4 allele of ApoE is the only confirmed and consistently replicated risk factor for late onset AD. ApoE is also a key ligand for LRP, a major neuronal LDL receptor. Despite the considerable converging evidence that implicates ApoE and LRP in the pathogenesis of AD, the precise mechanism by which ApoE and LRP modulate the risk for AD remains elusive. Moreover, studies investigating expression of ApoE and LRP in AD brain have reported variable and contradictory results. To overcome these inconsistencies, we studied the mRNA expression of ApoE and LRP in the postmortem brain of persons who died at different stages of dementia and AD-associated neuropathology relative to controls by qPCR and Western blotting. Clinical dementia rating scores were used as a measure of dementia severity, whereas, Braak neuropathological staging and neuritic plaque density were used as indices of the neuropathological progression of AD. ApoE and LRP mRNA expression was significantly elevated in the postmortem inferior temporal gyrus (area 20) and the hippocampus from individuals with dementia compared to those with intact cognition. In addition to their strong association with the progression of cognitive dysfunction, LRP and ApoE mRNA levels were also positively correlated with increasing neuropathological hallmarks of AD. Additionally, Western blot analysis of ApoE protein expression in the hippocampus showed that the differential expression observed at the transcriptional level is also reflected at the protein level. Given the critical role played by LRP and ApoE in Aβ and cholesterol trafficking, increased expression of LRP and ApoE may not only disrupt cholesterol homeostasis but may also contribute to some of the neurobiological features of AD, including plaque deposition.
doi:10.1016/j.neurobiolaging.2011.04.010
PMCID: PMC3234309  PMID: 21676498
4.  Increased expression of cholesterol transporter ABCA1 is highly correlated with severity of dementia in AD hippocampus 
Brain research  2010;1318C:167-177.
To gain insight into ATP-binding cassette transporter A1 (ABCA1) function and its potential role in AD pathology, we analyzed the expression of the cholesterol transporter ABCA1 in postmortem hippocampus from persons at different stages of dementia and AD associated neuropathology relative to cognitively intact normal donors by quantitative polymerase chain reaction (qPCR) and Western blot. In this study clinical dementia rating (CDR) scores were used as a measure of dementia severity, whereas, Braak neuropathological staging and neuritic plaque density were used as an index of the neuropathological progression of AD. Correlation analysis showed that ABCA1 mRNA expression was significantly elevated at the earliest recognizable stage of dementia compared to persons with intact cognition. ABCA1 mRNA was also positively correlated with Braak neuropathological stages and neuritic plaque density counts. Additionally, ABCA1 mRNA levels showed robust correlation with dementia severity even after controlling for the confounding contribution of accompanying neuropathological parameters to ABCA1 mRNA expression. Western blot analyses showed that the differential expression observed at the transcriptional level is also reflected at the protein level. Thus, our study provides transcriptional and translational evidence that the expression of ABCA1, a key modulator of cholesterol transport across the plasma membrane, is dysregulated in the AD brain and that this dysregulation is associated with increasing severity of AD, whether measured functionally as dementia severity or neuropathologically as increased neuritic plaque and neurofibrillary tangle density.
doi:10.1016/j.brainres.2010.01.006
PMCID: PMC2826590  PMID: 20079340
5.  CARDIOVASCULAR RISK FACTORS AFFECT HIPPOCAMPAL MICROVASCULATURE IN EARLY AD 
Translational neuroscience  2010;1(4):292-299.
There is growing clinical and neuropathologic evidence suggesting that cognitive decline in early Alzheimer’s disease (AD) is aggravated by a synergistic relationship between AD and cerebrovascular disease associated with cardiovascular risk factors such as diabetes and hypertension. Here we used the stereologic “Space Balls” method to investigate the relationships between AD pathology and cardiovascular risk factors in postmortem human brains of patients with hypertension and diabetes in two groups – one consisting of cases with AD diagnosis and one of cases without. Hippocampal CA1 and CA3 microvasculature length density estimates were generated to characterize quantitatively the contribution of cardiovascular risk factors to the severity of neuropathologic changes. Our main finding is that the mean and variance of length density values in the AD group were significantly increased from the non-AD group, regardless of the absence or presence of a cardiovascular risk factor. An additional finding is that in the AD group without a risk factor, dementia severity correlated with amount of length density change in the CA1 field—this correlation did not exist in the AD groups with risk factors. Our findings suggest a role for cardiovascular risk factors in quantifiable change of hippocampal CA1 field microvasculature, as well as suggest a possible role of cardiovascular risk factors in altering microvasculature pathology in the presence of AD.
PMCID: PMC3039302  PMID: 21331351
Stereology; Space Balls; Cardiovascular risk factors; CA1; CA3; Alzheimer’s disease
6.  Changes in dendritic complexity and spine morphology in transgenic mice expressing human wild-type tau 
Brain structure & function  2010;214(2-3):161-179.
Neurofibrillary tangles (NFTs) are composed of insoluble, hyperphosphorylated aggregates of the microtubule-associated protein tau and are present in various neurodegenerative diseases, including Alzheimer’s disease (AD). To investigate how tau affects neuronal function during NFT formation and subsequent neurodegeneration, we examined the morphology, spine density, spine type, and spine volume of layer III pyramidal neurons from the prefrontal cortex of mice expressing wild-type human tau (htau) over time. There were no significant alterations in apical dendritic arbor length in 3-, 6-, and 12-month-old htau mice; however, 12-month-old mice exhibited more complex arborization patterns. In addition, we observed a shift in spine morphology with fewer mushroom and more thin spines in both apical and basal dendrites as a function of htau accumulation. Interestingly, there was an overall decrease in volume of spines from 3 to 12 months. However, the volume of mushroom spines decreased from 3 to 6 months and increased from 6 to 12 months. This increase in complexity and branching in 12-month-old mice and the increase of volume of mushroom spines may represent compensatory mechanisms in the remaining intact neurons. As such, the accumulation of phosphorylated tau over time may contribute to the cognitive decline observed in AD by affecting neuronal structure and synaptic properties. Such alterations in dendrites and spines may result in the deterioration of neuronal function observed in AD, and provide a morphologic substrate for the relationship between synaptic integrity and cognitive decline.
doi:10.1007/s00429-010-0245-1
PMCID: PMC3032082  PMID: 20213269
Alzheimer’s disease; Neurofibrillary tangles; Tau; Transgenic mice; Dendrites; Spines
7.  Increased expression of RXRα in dementia: an early harbinger for the cholesterol dyshomeostasis? 
Background
Cholesterol content of cerebral membranes is tightly regulated by elaborate mechanisms that balance the level of cholesterol synthesis, uptake and efflux. Among the conventional regulatory elements, a recent research focus has been nuclear receptors, a superfamily of ligand-activated transcription factors providing an indispensable regulatory framework in controlling cholesterol metabolism pathway genes. The mechanism of transcriptional regulation by nuclear receptors such as LXRs involves formation of heterodimers with RXRs. LXR/RXR functions as a sensor of cellular cholesterol concentration and mediates cholesterol efflux by inducing the transcription of key cholesterol shuffling vehicles namely, ATP-binding cassette transporter A1 (ABCA1) and ApoE.
Results
In the absence of quantitative data from humans, the relevance of expression of nuclear receptors and their involvement in cerebral cholesterol homeostasis has remained elusive. In this work, new evidence is provided from direct analysis of human postmortem brain gene and protein expression suggesting that RXRα, a key regulator of cholesterol metabolism is differentially expressed in individuals with dementia. Importantly, RXRα expression showed strong association with ABCA1 and ApoE gene expression, particularly in AD vulnerable regions.
Conclusions
These findings suggest that LXR/RXR-induced upregulation of ABCA1 and ApoE levels may be the molecular determinants of cholesterol dyshomeostasis and of the accompanying dementia observed in AD.
doi:10.1186/1750-1326-5-36
PMCID: PMC2949865  PMID: 20843353
8.  Novel cerebrovascular pathology in mice fed a high cholesterol diet 
Background
Hypercholesterolemia causes atherosclerosis in medium to large sized arteries. Cholesterol is less known for affecting the microvasculature and has not been previously reported to induce microvascular pathology in the central nervous system (CNS).
Results
Mice with a null mutation in the low-density lipoprotein receptor (LDLR) gene as well as C57BL/6J mice fed a high cholesterol diet developed a distinct microvascular pathology in the CNS that differs from cholesterol-induced atherosclerotic disease. Microvessel diameter was increased but microvascular density and length were not consistently affected. Degenerative changes and thickened vascular basement membranes were present ultrastructurally. The observed pathology shares features with the microvascular pathology of Alzheimer's disease (AD), including the presence of string-like vessels. Brain apolipoprotein E levels which have been previously found to be elevated in LDLR-/- mice were also increased in C57BL/6J mice fed a high cholesterol diet.
Conclusion
In addition to its effects as an inducer of atherosclerosis in medium to large sized arteries, hypercholesterolemia also induces a microvascular pathology in the CNS that shares features of the vascular pathology found in AD. These observations suggest that high cholesterol may induce microvascular disease in a range of CNS disorders including AD.
doi:10.1186/1750-1326-4-42
PMCID: PMC2774302  PMID: 19852847
9.  Dietary composition modulates brain mass and solubilizable Aβ levels in a mouse model of aggressive Alzheimer's amyloid pathology 
Objective
Alzheimer's disease (AD) is a progressive neurodegenerative disease of the central nervous system (CNS). Recently, an increased interest in the role diet plays in the pathology of AD has resulted in a focus on the detrimental effects of diets high in cholesterol and fat and the beneficial effects of caloric restriction. The current study examines how dietary composition modulates cerebral amyloidosis and neuronal integrity in the TgCRND8 mouse model of AD.
Methods
From 4 wks until 18 wks of age, male and female TgCRND8 mice were maintained on one of four diets: (1) reference (regular) commercial chow; (2) high fat/low carbohydrate custom chow (60 kcal% fat/30 kcal% protein/10 kcal% carbohydrate); (3) high protein/low carbohydrate custom chow (60 kcal% protein/30 kcal% fat/10 kcal% carbohydrate); or (4) high carbohydrate/low fat custom chow (60 kcal% carbohydrate/30 kcal% protein/10 kcal% fat). At age 18 wks, mice were sacrificed, and brains studied for (a) wet weight; (b) solubilizable Aβ content by ELISA; (c) amyloid plaque burden; (d) stereologic analysis of selected hippocampal subregions.
Results
Animals receiving a high fat diet showed increased brain levels of solubilizable Aβ, although we detected no effect on plaque burden. Unexpectedly, brains of mice fed a high protein/low carbohydrate diet were 5% lower in weight than brains from all other mice. In an effort to identify regions that might link loss of brain mass to cognitive function, we studied neuronal density and volume in hippocampal subregions. Neuronal density and volume in the hippocampal CA3 region of TgCRND8 mice tended to be lower in TgCRND8 mice receiving the high protein/low carbohydrate diet than in those receiving the regular chow. Neuronal density and volume were preserved in CA1 and in the dentate gyrus.
Interpretation
Dissociation of Aβ changes from brain mass changes raises the possibility that diet plays a role not only in modulating amyloidosis but also in modulating neuronal vulnerability. However, in the absence of a study of the effects of a high protein/low carbohydrate diet on nontransgenic mice, one cannot be certain how much, if any, of the loss of brain mass exhibited by high protein/low carbohydrate diet-fed TgCRND8 mice was due to an interaction between cerebral amyloidosis and diet. Given the recent evidence that certain factors favor the maintenance of cognitive function in the face of substantial structural neuropathology, we propose that there might also exist factors that sensitize brain neurons to some forms of neurotoxicity, including, perhaps, amyloid neurotoxicity. Identification of these factors could help reconcile the poor clinicopathological correlation between cognitive status and structural neuropathology, including amyloid pathology.
doi:10.1186/1750-1326-4-40
PMCID: PMC2775731  PMID: 19845940

Results 1-9 (9)