Convergent and Discriminant Validity of Default Mode Network and Limbic Network Perfusion in Amnestic Mild Cognitive Impairment Patients.

BACKGROUND: Previous studies reported default mode network (DMN) and limbic network (LIN) brain perfusion deficits in patients with amnestic mild cognitive impairment (aMCI), frequently a prodromal stage of Alzheimer's disease (AD). However, the validity of these measures as AD markers has not yet been tested using MRI arterial spin labeling (ASL). OBJECTIVE: To investigate the convergent and discriminant validity of DMN and LIN perfusion in aMCI. METHODS: We collected core AD markers (amyloid-ß 42 [Aß42], phosphorylated tau 181 levels in cerebrospinal fluid [CSF]), neurodegenerative (hippocampal volumes and CSF total tau), vascular (white matter hyperintensities), genetic (apolipoprotein E [APOE] status), and cognitive features (memory functioning on Paired Associate Learning test [PAL]) in 14 aMCI patients. Cerebral blood flow (CBF) was extracted from DMN and LIN using ASL and correlated with AD features to assess convergent validity. Discriminant validity was assessed carrying out the same analysis with AD-unrelated features, i.e., somatomotor and visual networks' perfusion, cerebellar volume, and processing speed. RESULTS: Perfusion was reduced in the DMN (F = 5.486, p = 0.039) and LIN (F = 12.678, p = 0.004) in APOE ɛ4 carriers compared to non-carriers. LIN perfusion correlated with CSF Aß42 levels (r = 0.678, p = 0.022) and memory impairment (PAL, number of errors, r = -0.779, p = 0.002). No significant correlation was detected with tau, neurodegeneration, and vascular features, nor with AD-unrelated features. CONCLUSION: Our results support the validity of DMN and LIN ASL perfusion as AD markers in aMCI, indicating a significant correlation between CBF and amyloidosis, APOE ɛ4, and memory impairment.

Ongoing Electroencephalographic Rhythms Related to Exploratory Movements in Transgenic TASTPM Mice.

BACKGROUND: The European PharmaCog study (http://www.pharmacog.org) has reported a reduction in delta (1-6 Hz) electroencephalographic (EEG) power (density) during cage exploration (active condition) compared with quiet wakefulness (passive condition) in PDAPP mice (hAPP Indiana V717F mutation) modeling Alzheimer's disease (AD) amyloidosis and cognitive deficits. OBJECTIVE: Here, we tested the reproducibility of that evidence in TASTPM mice (double mutation in APP KM670/671NL and PSEN1 M146V), which develop brain amyloidosis and cognitive deficits over aging. The reliability of that evidence was examined in four research centers of the PharmaCog study. METHODS: Ongoing EEG rhythms were recorded from a frontoparietal bipolar channel in 29 TASTPM and 58 matched "wild type" C57 mice (range of age: 12-24 months). Normalized EEG power was calculated. Frequency and amplitude of individual delta and theta frequency (IDF and ITF) peaks were considered during the passive and active conditions. RESULTS: Compared with the "wild type" group, the TASTPM group showed a significantly lower reduction in IDF power during the active over the passive condition (p < 0.05). This effect was observed in 3 out of 4 EEG recording units. CONCLUSION: TASTPM mice were characterized by "poor reactivity" of delta EEG rhythms during the cage exploration in line with previous evidence in PDAPP mice. The reliability of that result across the centers was moderate, thus unveiling pros and cons of multicenter preclinical EEG trials in TASTPM mice useful for planning future studies.

Primary fatty amides in plasma associated with brain amyloid burden, hippocampal volume, and memory in the European Medical Information Framework for Alzheimer's Disease biomarker discovery cohort.

INTRODUCTION: A critical and as-yet unmet need in Alzheimer's disease (AD) is the discovery of peripheral small molecule biomarkers. Given that brain pathology precedes clinical symptom onset, we set out to test whether metabolites in blood associated with pathology as indexed by cerebrospinal fluid (CSF) AD biomarkers. METHODS: This study analyzed 593 plasma samples selected from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery study, of individuals who were cognitively healthy (n = 242), had mild cognitive impairment (n = 236), or had AD-type dementia (n = 115). Logistic regressions were carried out between plasma metabolites (n = 883) and CSF markers, magnetic resonance imaging, cognition, and clinical diagnosis. RESULTS: Eight metabolites were associated with amyloid ß and one with t-tau in CSF, these were primary fatty acid amides (PFAMs), lipokines, and amino acids. From these, PFAMs, glutamate, and aspartate also associated with hippocampal volume and memory. DISCUSSION: PFAMs have been found increased and associated with amyloid ß burden in CSF and clinical measures.

Ongoing Electroencephalographic Activity Associated with Cortical Arousal in Transgenic PDAPP Mice (hAPP V717F).

BACKGROUND: It has been shown that theta (6-10 Hz) and delta (1-6 Hz) ongoing electroencephalographic (EEG) rhythms revealed variations in the cortical arousal in C57 Wild Type (WT) mice during cage exploration (active condition) compared to awake quiet behavior (passive condition; IMI PharmaCog project, www.pharmacog.eu). OBJECTIVE: The objective was to test if these EEG rhythms might be abnormal in old PDAPP mice modeling Alzheimer's disease (AD) with a hAPP Indiana V717F mutation (They show abnormal neural transmission, cognitive deficits, and brain accumulation of Aß1-42). METHODS: Ongoing EEG rhythms were recorded by a frontoparietal bipolar channel in 15 PDAPP and 23 WT C57 male mice (mean age of 22.8 months ±0.4 and 0.3 standard error, respectively). EEG absolute power (density) was calculated. Frequency and amplitude of individual delta and theta frequency (IDF and ITF) peaks were considered during passive and active states in the wakefulness. RESULTS: Compared with the WT group, the PDAPP group showed higher frequency of the IDF during the passive condition and lower frequency of the ITF during the active state. Furthermore, the WT but not PDAPP group showed significant changes in the frontoparietal EEG power (IDF, ITF) during active over passive state. CONCLUSION: PDAPP mice were characterized by less changes in the brain arousal during an active state as revealed by frontoparietal EEG rhythms. Future studies will have to cross-validate the present results on large animal groups, clarify the neurophysiological underpinning of the effect, and test if the disease modifying drugs against AD amyloidosis normalize those candiate EEG biomarkers in PDAPP mice.

Longitudinal Characterization of [18F]-FDG and [18F]-AV45 Uptake in the Double Transgenic TASTPM Mouse Model.

We aimed to monitor the timing of amyloid-ß deposition in relation to changes in brain function using in vivo imaging with [18F]-AV45 and [18F]-FDG in a mouse model of Alzheimer's disease. TASTPM transgenic mice and wild-type controls were scanned longitudinally with [18F]-AV45 and [18F]-FDG before (3 months of age) and at multiple time points after the onset of amyloid deposition (6, 9, 12, and 15 months of age). As expected with increasing amyloidosis, TASTPM mice demonstrated progressive age-dependent increases in [18F]-AV45 uptake that were significantly higher than for WT from 9 months onwards and correlated to ex vivo measures of amyloid burden. The metabolism of [18F]-AV45 produces several brain penetrant radiometabolites and normalization to a reference region helps to negate this non-specific binding and improve the sensitivity of [18F]-AV45. The observed trajectory of [18F]-FDG alterations deviated from our proposed hypothesis of gradual decreases with worsening amyloidosis. While [18F]-FDG uptake in TASTPM mice was significantly lower than that of WT at 9 months, reduced [18F]-FDG was not associated with aging in TASTPM mice. Moreover, [18F]-FDG uptake did not correlate to measures of ex vivo amyloid burden. Our findings suggest that while amyloid-ß is sufficient to induce hypometabolism, these pathologies are not linked in a dose-dependent manner in TASTPM mice.

Quantitative µPET Imaging of Cerebral Glucose Metabolism and Amyloidosis in the TASTPM Double Transgenic Mouse Model of Alzheimer's Disease.

Positron emission tomography studies of cerebral glucose utilization and amyloid-ß deposition with fluoro-deoxy-D-glucose ([(18)F]-FDG) and amyloid tracers have shown characteristic pathological changes in Alzheimer's Disease that can be used for disease diagnosis and monitoring. Application of this technology to preclinical research with transgenic animal models would greatly facilitate drug discovery and further understanding of disease processes. The results from preclinical studies with these imaging biomarkers have however been highly inconsistent, causing doubts over whether animal models can truly replicate an AD-like phenotype. In this study we performed in vivo imaging with [(18)F]-FDG and [(18)F]-AV45 in double transgenic TASTPM mice, a transgenic model that been previously demonstrated high levels of fibrillar amyloid-ß and decreases in cerebral glucose utilization with ex vivo techniques. Our results show widespread and significant retention of [(18)F]-AV45 (p < 0.0001) in aged TASTPM mice in addition to significant regional decreases in [(18)F]-FDG uptake (p < 0.05). In vivo quantification of amyloid-ß showed a strong (Pearson's r = 0.7078), but not significant (p = 0.1156), positive correlation with ex vivo measures suggesting some limitations on tracer sensitivity. In the case of [(18)F]-FDG, voxelwise analysis greatly enhanced detection of hypometabolic regions. We further evidenced modest neuronal loss (thalamus p = 0.0318) that could underlie the observed hypometabolism. This research was performed in conjunction with the European Community's Seventh Framework Program (FP7/2007-2013) for the Innovative Medicine Initiative under the PharmaCog Grant Agreement no.115009.

Dietary (-)-epicatechin as a potent inhibitor of ßγ-secretase amyloid precursor protein processing.

Flavonoids, a group of dietary polyphenols have been shown to possess cognitive health benefits. Epidemiologic evidence suggests that they could play a role in risk reduction in dementia. Amyloid precursor protein processing and the subsequent generation of amyloid beta (Aß) are central to the pathogenesis of Alzheimer's disease, as soluble, oligomeric Aß is thought to be the toxic species driving disease progression. We undertook an in vitro screen to identify flavonoids with bioactivity at ßγ-mediated amyloid precursor protein processing, which lead to identification of a number of flavonoids bioactive at 100 nM. Because of known bioavailability, we investigated the catechin family further and identified epigallocatechin and (-)-epicatechin as potent (nanomolar) inhibitors of amyloidogenic processing. Supporting this finding, we have shown reduced Aß pathology and Aß levels following short term, a 21-day oral delivery of (-)-epicatechin in 7-month-old TASTPM mice. Further, in vitro mechanistic studies suggest this is likely because of indirect BACE1 inhibition. Taken together, our results suggest that orally delivered (-)-epicatechin may be a potential prophylactic for Alzheimer's disease.

Focal expression of adeno-associated viral-mutant tau induces widespread impairment in an APP mouse model.

Adeno-associated virus serotype 6 (AAV6) viral vectors encoding mutant and normal tau were used to produce focal tau pathology. Two mutant forms of tau were used; the P301S tau mutation is associated with neurofibrillary tangle formation in humans, and the 3PO mutation leads to rapid tau aggregation and is associated with pathogenic phosphorylation and cytotoxicity in vitro. We show that adeno-associated viral injection into entorhinal cortex of normal and tau knockout animals leads to local overexpression of tau, and the presence of human tau in axons projecting to and emanating from the entorhinal cortex. Starting at 2 months and increasing by 6 months post-injection neurons expressing mutant tau developed hyperphosphorylated tau pathology, in addition to dystrophic neurites. There was neuronal loss in tau-expressing regions, which was similar in normal and in TASTPM mice injected with mutant tau. There was neuroinflammation around plaques, and in regions expressing mutant tau. We saw no evidence that mutant tau had affected amyloid-beta pathology or vice versa. Morris water maze behavioral tests demonstrated mild memory impairment attributable to amyloid-beta pathology at 2 and 4 months, with severe impairment at 6 months in animals receiving adeno-associated viral-3PO. Therefore, TASTPM mice injected with mutant tau displayed many of the main features characteristic of human Alzheimer's disease patients and might be used as a model to test new drugs to ameliorate clinical features of Alzheimer's disease.

Bone marrow-derived mesenchymal stem cells contribute to the reduction of amyloid-ß deposits and the improvement of synaptic transmission in a mouse model of pre-dementia Alzheimer's disease.

The remarkable potentiality of bone marrow-derived mesenchymal stem cells (BM-MSCs) after transplantation to models of neurological disease and injury has been described. We have previously published data confirming the influence of BM-MSCs on ß-amyloid (Aß) deposition in an Alzheimer's disease (AD) mouse model. However, therapeutic approaches in neurological diseases such as AD, including those for BM-MSCs, are increasingly centered on the potential for prophylactic therapy in pro-dromal states where the underlying cause of the disease is apparent but functional deficits are not. In order to investigate whether BM-MSCs could have a beneficial effect in high-risk pre-dementia AD individuals, we treated young AD mice, at an age at which they display neuropathological, but not cognitive features of AD. Following a single intra-cerebral injection of BM-MSCs, interestingly, we found a significant decrease in the cerebral Aß deposition compared with controls treated with PBS that was sustained up to 2 months post-injection. Expression of dynamin 1 and Synapsin 1, key pre-synaptic proteins associated with synaptic transmission, which are typically decreased in brains of AD patients, were considerably enhanced in the brains of AD mice treated with BM-MSCs and this response was sustained beyond 2 months. These data demonstrate that BM-MSCs produce an acute reduction in Aß deposits and facilitate changes in key proteins required for synaptic transmission. These findings suggest that BM-MSC transplantation warrants further investigation as a potential therapy for early intervention in pro-dromal AD.

Effects of genetic variation in the P2RX7 gene on pharmacodynamics of a P2X(7) receptor antagonist: a prospective genotyping approach.

AIMS: To investigate the effects of two single nucleotide polymorphisms (SNPs) in the human P2X7 receptor gene (P2RX7)--1068G>A (A348T) and 1513A>C (E496A)--on P2X7 receptor function, using a specific receptor antagonist (GSK1370319A) and prospective genetic stratification. METHODS: Lipopolysaccharide- and ATP-stimulated interleukin-1ß production was determined in the presence or absence of GSK1370319A in blood culture from 32 prospectively genotyped subjects. RESULTS: There was approximately 6.7-fold difference (P < 0.0001) in IC50 for inhibition of ATP-stimulated interleukin-1ß release by GSK1370319A between individuals with the homozygous gain--(1068A) and loss-of-function (1513C) genotypes (expressing the 348T, 496E and 348A, 496A alleles, respectively). CONCLUSIONS: Leukocyte P2X7 receptors had significantly altered pharmacodynamic responses to a specific antagonist (GSK1370319A), directly related to SNP genotype.

The neuroprotective effect of a specific P2X7 receptor antagonist derives from its ability to inhibit assembly of the NLRP3 inflammasome in glial cells.

Release of interleukin (IL)-1ß from immunocompetent cells requires formation of the NACHT, LLR and PYD domains-containing protein 3 (NLRP3) inflammasome and caspase 1 activation. Adenosine 5'-triphosphate (ATP), acting on the P2X(7) receptor, is one factor that stimulates inflammasome assembly. We show that a novel specific P2X(7) receptor antagonist, GSK1370319A, inhibits ATP-induced increase in IL-1ß release and caspase 1 activation in lipopolysaccharide (LPS)-primed mixed glia by blocking assembly of the inflammasome in a pannexin 1-dependent manner. GSK1370319A also inhibits ATP-induced subregion-specific neuronal loss in hippocampal organotypic slice cultures, which is dependent on its ability to prevent inflammasome assembly in glia. Significantly, GSK1370319A attenuates age-related deficits in long-term potentiation (LTP) and inhibits the accompanying age-related caspase 1 activity. We conclude that inhibiting P2X(7) receptor-activated NLRP3 inflammasome formation and the consequent IL-1ß release from glia preserve neuronal viability and synaptic activity.

Rosiglitazone attenuates the age-related changes in astrocytosis and the deficit in LTP.

Neuroinflammation is a significant and consistent feature of many neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). The greatest risk factor for neurodegenerative disorders is age and a proinflammatory phenotype in the aged brain is believed to contribute to these neurodegenerative conditions. In animal models, neuroinflammatory changes, characterized by increased microglial activation, have been associated with a loss of synaptic plasticity and here we show that treatment of aged rats with the PPARγ agonist, rosiglitazone, modulates the inflammatory changes and restores synaptic function. The evidence presented highlights an important role for astrocytes in inducing inflammatory changes and suggests that the age-related astrogliosis and astrocytosis is responsible for the increase in the proinflammatory cytokine, tumor necrosis factor alpha (TNF-α). Magnetic resonance (MR) imaging revealed an age-related increase in T1 relaxation time and, importantly, treatment of aged rats with rosiglitazone reversed the age-related increases in astrogliosis and astrocytosis, TNF-α concentration and T1 relaxation time. The evidence indicates that the site of action for rosiglitazone is endothelial cells, and suggests that its effect on astrocytes is secondary to its effect on endothelial cells.

A PPARdelta agonist reduces amyloid burden and brain inflammation in a transgenic mouse model of Alzheimer's disease.

Agonists of the peroxisome proliferator activated receptor gamma (PPARgamma) have been shown to reduce inflammatory responses in several animal models of neurological diseases and conditions and to reduce amyloid burden in transgenic mice expressing mutant forms of human amyloid precursor protein. However, the effects of activating the related receptor PPARdelta (PPARdelta), which is expressed at higher levels in the brain than PPARgamma, on inflammation and amyloid burden have not been explored. In this study we tested the effects of the selective PPARdelta agonist GW742 in 5xFAD mice which harbor 3 mutations in amyloid precursor protein and 2 mutations in presenilin 1, develop plaques by 5-6 weeks of age, and show robust inflammation and neuronal damage. Oral delivery of GW742 significantly reduced amyloid plaque burden in the subiculum region of 3-month old male and female 5xFAD mice. GW742 also significantly reduced astrocyte activation, suggesting anti-inflammatory effects on glia cells. The changes in plaque burden were accompanied by increased expression of the amyloid degrading enzymes neprilysin and insulin degrading enzyme, while in transfected HEK293 cells, GW742 activated a neprilysin promoter driving luciferase expression. These results suggest that, as found for some PPARgamma agonists, PPARdelta agonists can also reduce amyloid burden likely to be mediated by effects on amyloid clearance.

Lymphocytes from P2X7-deficient mice exhibit enhanced P2X7 responses.

The purinergic receptor P2X(7) is expressed on immune cells, and its stimulation results in the release of IL-1beta from macrophages. Its absence, as evidenced from the analysis of two independent strains of P2X(7)-deficient mice, results in reduced susceptibility to inflammatory disease, and the molecule is an important, potential therapeutic target in autoimmunity. However, P2X(7) has also been detected in several neuronal cell types, although its function and even its presence in these cells are highly contested, with anti-P2X(7) antibodies staining brain tissue from both strains of P2X(7)(-/-) mice identically to wild-type mice. It has therefore been suggested that neurons express a distinct "P2X(7)-like" protein that has similar antibody recognition epitopes to P2X(7) and some properties of the genuine receptor. In this study, we show that whereas P2X(7) activity is absent from macrophages and dendritic cells in P2X(7)(-/-) animals, T cells from one gene-deficient strain unexpectedly exhibit higher levels of P2X(7) activity than that found in cells from control, unmanipulated C57BL/6 mice. A potential mechanism for this tissue-specific P2X(7) expression in P2X(7)(-/-) animals is discussed, as is the implication that the immune and indeed neuronal functions of P2X(7) may have been underestimated.

Longitudinal regional brain volume changes quantified in normal aging and Alzheimer's APP x PS1 mice using MRI.

In humans, mutations of amyloid precursor protein (APP) and presenilins (PS) 1 and 2 are associated with amyloid deposition, brain structural change and cognitive decline, like in Alzheimer's disease (AD). Mice expressing these proteins have illuminated neurodegenerative disease processes but, unlike in humans, quantitative imaging has been little used to systematically determine their effects, or those of normal aging, on brain structure in vivo. Accordingly, we investigated wildtype (WT) and TASTPM mice (expressing human APP(695(K595N, M596L)) x PS1(M146V)) longitudinally using MRI. Automated global and local image registration, allied to a standard digital atlas, provided pairwise segmentation of 13 brain regions. We found the mature mouse brain, unlike in humans, enlarges significantly from 6-14 months old (WT 3.8+/-1.7%, mean+/-SD, P<0.0001). Significant changes were also seen in other WT brain regions, providing an anatomical benchmark for comparing other mouse strains and models of brain disorder. In TASTPM, progressive amyloidosis and astrogliosis, detected immunohistochemically, reflected even larger whole brain changes (5.1+/-1.4%, P<0.0001, transgenexage interaction P=0.0311). Normalising regional volumes to whole brain measurements revealed significant, prolonged, WT-TASTPM volume differences, suggesting transgene effects establish at <6 months old of age in most regions. As in humans, gray matter-rich regions decline with age (e.g. thalamus, cerebral cortex and caudoputamen); ventricles and white matter (corpus callosum, corticospinal tract, fornix system) increase; in TASTPMs such trends often varied significantly from WT (especially hippocampus). The pervasive, age-related structural changes between WT and AD transgenic mice (and mouse and human) suggest subtle but fundamental species differences and AD transgene effects.

Identification of miRNA changes in Alzheimer's disease brain and CSF yields putative biomarkers and insights into disease pathways.

MicroRNAs have essential functional roles in brain development and neuronal specification but their roles in neurodegenerative diseases such as Alzheimer's disease (AD) is unknown. Using a sensitive qRT-PCR platform we identified regional and stage-specific deregulation of miRNA expression in AD patient brains. We used experimental validation in addition to literature to reveal how the deregulated brain microRNAs are biomarkers for known and novel pathways in AD pathogenesis related to amyloid processing, neurogenesis, insulin resistance, and innate immunity. We additionally recovered miRNAs from cerebrospinal fluid and discovered AD-specific miRNA changes consistent with their role as potential biomarkers of disease.

Proteomic identification and early validation of complement 1 inhibitor and pigment epithelium-derived factor: Two novel biomarkers of Alzheimer's disease in human plasma.

Emerging disease modifying therapeutic strategies for Alzheimer's disease (AD) have generated a critical need for biomarkers of early stage disease. Here, we describe the identification and assessment of a number of candidate biomarkers in patients with mild to moderate probable AD. Plasma from 47 probable Alzheimer's patients and 47 matched controls were analysed by proteomics to define a significant number of proteins whose expression appeared to be associated with AD. These were compared to a similar proteomic comparison of a mouse transgenic model of amyloidosis, which showed encouraging overlap with the human data. From these studies a prioritised list of 31 proteins were then analysed by immunoassay and/or functional assay in the same human cohort to verify the changes observed. Eight proteins continued to show significance by either immunoassay or functional assay in the human plasma and these were tested in a further set of 100 probable AD patients and 100 controls from the original cohort. From our data it appeared that two proteins, serpin F1 (pigment epithelium-derived factor) and complement C1 inhibitor are down-regulated in plasma from AD patients.

Neuroprotective actions of noradrenaline: effects on glutathione synthesis and activation of peroxisome proliferator activated receptor delta.

The endogenous neurotransmitter noradrenaline (NA) can protect neurons from the toxic consequences of various inflammatory stimuli, however the exact mechanisms of neuroprotection are not well known. In the current study, we examined neuroprotective effects of NA in primary cultures of rat cortical neurons. Exposure to oligomeric amyloid beta (Abeta) 1-42 peptide induced neuronal damage revealed by increased staining with fluorojade, and toxicity assessed by LDH release. Abeta-dependent neuronal death did not involve neuronal expression of the inducible nitric oxide synthase 2 (NOS2), since Abeta did not induce nitrite production from neurons, LDH release was not reduced by co-incubation with NOS2 inhibitors, and neurotoxicity was similar in wildtype and NOS2 deficient neurons. Co-incubation with NA partially reduced Abeta-induced neuronal LDH release, and completely abrogated the increase in fluorojade staining. Treatment of neurons with NA increased expression of gamma-glutamylcysteine ligase, reduced levels of GSH peroxidase, and increased neuronal GSH levels. The neuroprotective effects of NA were partially blocked by co-treatment with an antagonist of peroxisome proliferator activated receptors (PPARs), and replicated by incubation with a selective PPARdelta (PPARdelta) agonist. NA also increased expression and activation of PPARdelta. Together these data demonstrate that NA can protect neurons from Abeta-induced damage, and suggest that its actions may involve activation of PPARdelta and increases in GSH production.

Rosiglitazone induces mitochondrial biogenesis in mouse brain.

Rosiglitazone was found to simulate mitochondrial biogenesis in mouse brain in an apolipoprotein (Apo) E isozyme-independent manner. Rosiglitazone induced both mitochondrial DNA (mtDNA) and estrogen-stimulated related receptor alpha (ESRRA) mRNA, a key regulator of mitochondrial biogenesis. Transcriptomics and proteomics analysis suggested the mitochondria produced in the presence of human ApoE3 and E4 were not as metabolically efficient as those in the wild type or ApoE knockout mice. Thus, we propose that PPARgamma agonism induces neuronal mitochondrial biogenesis and improves glucose utilization leading to improved cellular function and provides mechanistic support for the improvement in cognition observed in treatment of Alzheimer's patients with rosiglitazone.

Non-cognitive behaviours in an APP/PS1 transgenic model of Alzheimer's disease.

Alzheimer's disease (AD) is characterised by progressive cognitive impairment with neuropsychiatric symptoms such as anomalous motor behaviour, depression, anxiety, weight loss, irritability and agitation. The effect of hAPP and PS1 overexpression on cognition has been well characterised in a variety of transgenic mouse models, however, non-cognitive behaviours have not been considered as systematically. The non-cognitive behaviour of the hAPP/PS1 transgenic mouse model (TASTPM) was observed at ages spanning the rapid progression of amyloid neuropathology. TASTPM transgenic mice, of both genders, exhibited decreased spontaneous motor activity, disinhibition, increased frequency and duration of feeding bouts, reduced body weight and, by 10 months, increased activity over a 24h period. In addition to the aforementioned behaviours, male transgenic mice also displayed enhanced aggression relative to wildtype controls. These data reveal previously unreported disease relevant behavioural changes that demonstrate the value of measuring behaviour in APP/PS1 transgenic models. These behavioural readouts could be useful in screening putative drug treatments for AD.