27 research outputs found
Ablation of the Locus Coeruleus Increases Oxidative Stress in Tg-2576 Transgenic but Not Wild-Type Mice
Mice transgenic for production of excessive or mutant forms of beta-amyloid differ from patients with Alzheimer's disease in the degree of inflammation, oxidative damage, and alteration of intermediary metabolism, as well as the paucity or absence of neuronal atrophy and cognitive impairment. Previous observers have suggested that differences in inflammatory response reflect a discrepancy in the state of the locus coeruleus (LC), loss of which is an early change in Alzheimer's disease but which is preserved in the transgenic mice. In this paper, we extend these observations by examining the effects of the LC on markers of oxidative stress and intermediary metabolism. We compare four groups: wild-type or Tg2576 Aβ transgenic mice injected with DSP4 or vehicle. Of greatest interest were metabolites different between ablated and intact transgenics, but not between ablated and intact wild-type animals. The Tg2576_DSP4 mice were distinguished from the other three groups by oxidative stress and altered energy metabolism. These observations provide further support for the hypothesis that Tg2576 Aβ transgenic mice with this ablation may be a more congruent model of Alzheimer's disease than are transgenics with an intact LC
A Dysregulated Endocannabinoid-Eicosanoid Network Supports Pathogenesis in a Mouse Model of Alzheimer's Disease
SummaryAlthough inflammation in the brain is meant as a defense mechanism against neurotoxic stimuli, increasing evidence suggests that uncontrolled, chronic, and persistent inflammation contributes to neurodegeneration. Most neurodegenerative diseases have now been associated with chronic inflammation, including Alzheimer's disease (AD). Whether anti-inflammatory approaches can be used to treat AD, however, is a major unanswered question. We recently demonstrated that monoacylglycerol lipase (MAGL) hydrolyzes endocannabinoids to generate the primary arachidonic acid pool for neuroinflammatory prostaglandins. In this study, we show that genetic inactivation of MAGL attenuates neuroinflammation and lowers amyloid β levels and plaques in an AD mouse model. We also find that pharmacological blockade of MAGL recapitulates the cytokine-lowering effects through reduced prostaglandin production, rather than enhanced endocannabinoid signaling. Our findings thus reveal a role of MAGL in modulating neuroinflammation and amyloidosis in AD etiology and put forth MAGL inhibitors as a potential next-generation strategy for combating AD
Pancortin-2 interacts with WAVE1 and Bcl-xL in a mitochondria-associated protein complex that mediates ischemic neuronal death
d-amphetamine and fixed-interval performance: effects of operant history.
Sixteen rats were initially exposed for 50 sessions to either a fixed-ratio 40 or an interresponse-time-greater-than-11-second food reinforcement schedule, then shifted to a fixed-interval 15-second food reinforcement schedule. Animals with fixed-ratio 40 histories lever pressed at much higher rates under the fixed-interval schedule than did animals with inter-response-time-greater-than-11-second histories. This difference persisted across 93 sessions of fixed-interval exposure. The effects of d=amphetamine were assessed after 15 and 59 sessions of fixed-interval exposure. On both occasions, the low-rate responding of animals with interresponse-time-greater-than-11-second histories was typically increased by all doses of the drug, while the high-rate responding of animals with fixed-ratio 40 histories was typically decreased by all doses of the drug. These results suggest that control response rate under the fixed-interval schedule, which may be affected by a history of responding under another schedule, is the primary determinant of the relative effects of d-amphetamine
Behavioral Characterization of A53T Mice Reveals Early and Late Stage Deficits Related to Parkinson’s Disease
<div><p>Parkinson's disease (PD) pathology is characterized by the formation of intra-neuronal inclusions called Lewy bodies, which are comprised of alpha-synuclein (α-syn). Duplication, triplication or genetic mutations in α-syn (A53T, A30P and E46K) are linked to autosomal dominant PD; thus implicating its role in the pathogenesis of PD. In both PD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of protein aggregates (i.e., α-syn) and neurodegeneration. Characterization of the timing and nature of symptomatic dysfunction is important for understanding the impact of α-syn on disease progression. Furthermore, this knowledge is essential for identifying pathways and molecular targets for therapeutic intervention. To this end, we examined various functional and morphological endpoints in the transgenic mouse model expressing the human A53T α-syn variant directed by the mouse prion promoter at specific ages relating to disease progression (2, 6 and 12 months of age). Our findings indicate A53T mice develop fine, sensorimotor, and synaptic deficits before the onset of age-related gross motor and cognitive dysfunction. Results from open field and rotarod tests show A53T mice develop age-dependent changes in locomotor activity and reduced anxiety-like behavior. Additionally, digigait analysis shows these mice develop an abnormal gait by 12 months of age. A53T mice also exhibit spatial memory deficits at 6 and 12 months, as demonstrated by Y-maze performance. In contrast to gross motor and cognitive changes, A53T mice display significant impairments in fine- and sensorimotor tasks such as grooming, nest building and acoustic startle as early as 1–2 months of age. These mice also show significant abnormalities in basal synaptic transmission, paired-pulse facilitation and long-term depression (LTD). Combined, these data indicate the A53T model exhibits early- and late-onset behavioral and synaptic impairments similar to PD patients and may provide useful endpoints for assessing novel therapeutic interventions for PD.</p></div
Neuroprotective Profile of Novel Src Kinase Inhibitors in Rodent Models of Cerebral Ischemia
Total and aggregated mutant alpha synuclein (α-syn) increases with age and onset of disease.
<p>Human specific α-syn was expressed in neurons and neuropil of A53T homozygote (top panel), but not wild type mice (bottom panel; A). Western blot analysis indicates human α-syn levels significantly increase with age in A53T brain (n = 6 per group; B). α-syn aggregates are rare but visible at 2 months, then accumulate with age; representative photo of proteinase-K resistant aggregates in A53T brain (pons region) at 2, 6 and 12 months (C). Kaplan-Meier survival curve illustrates onset of disease, as defined by motor disability, between 8–17 months in homozygous A53T mice (n = 30; D). Data normalized to actin and plotted as Mean+/− SEM. **p<0.001.</p
A53T mice exhibit age-related spatial memory deficits.
<p>Mice were allowed to explore two arms (start & familiar) of the Y-maze for five minutes (Trial 1). During this acclimation period, both wild type and A53T mice performed similarly when exploring (A) and entering (B) arms. The percent duration in each arm for 2 month old wild type mice was different than chance (#, 95% confidence interval; dotted line = 50%); however the overall entries and total time spent in arms were similar for both genotypes (data not shown). After a one-hour inter-trial interval, wild type mice of all ages and 2-month-old A53T mice spent significantly more time exploring (C) and entering (D) the novel arm of the Y-maze compared to the start or familiar arms. Conversely, 6 and 12 month old A53T mice did not show a preference for the novel arm, suggesting a disruption in spatial memory. There were no alterations in locomotor indices across genotype or age (not shown). Data plotted as Mean +/−SEM. To look for equal exploration of arms, data were compared to chance (depicted by dotted line; T1 = 50%, T2 = 33.3%) using the 95% confidence interval (<sup>#</sup>p<0.05). Unpaired t-test analysis was utilized for assessing differences between genotypes within age (*p<0.05). n = 11–15 per group; W = wild type, H = homozygote.</p
A53T mice elicit a reduced startle response at 2 months of age.
<p>The startle reflex response is significantly reduced in homozygous A53T mice relative to wild type controls at 2, 6 and 12 months (A). Results from the auditory brainstem response test suggest the reduction in startle is not due to hearing loss as there is no difference between wild type and A53T mice in hearing when exposed to frequencies of 8 and 16 kHz. In fact, A53T mice actually hear at a lower threshold when exposed to the 32 kHz frequency (N = 6 per group; 2 months of age) (B). Unless otherwise noted, graphs are representative of data collected from 2–3 independent cohorts of animals with 8–15 mice per group. Data plotted as Mean+/− SEM. Bonferonni post hoc test *p<0.05; **p<0.001; ***p<0.0001; kHz = kilohertz, dB = decibel, WT = Wild type, HO = Homozygous.</p