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Holly M. Brothers & Gary L. Wenk Department of Psychology The Ohio State University

The role of neuroinflammation in the determination of regional and neuronal vulnerability in Alzheimer’s disease. Holly M. Brothers & Gary L. Wenk Department of Psychology The Ohio State University Nothing to Disclose.

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Holly M. Brothers & Gary L. Wenk Department of Psychology The Ohio State University

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  1. The role of neuroinflammation in the determination of regional and neuronal vulnerability in Alzheimer’s disease Holly M. Brothers & Gary L. Wenk Department of Psychology The Ohio State University Nothing to Disclose

  2. Studies in our laboratory demonstrate that regional and cellularvulnerabilityin the brain are influenced by an interaction between: neuroinflammation, duration of inflammation, and gender.

  3. What initiates neuroinflammation?What are its consequences? Microglial activation is an early event in the pathogenesis of AD that appears in brain regions that later show the greatest degree of atrophy. Mutant Proteins Synaptic Loss/ Neuronal Death Dementia Symptoms Inflammation Cagnin et al., 2001

  4. LPS Chronic neuroinflammation model Infusion of lipopolysaccharide (LPS, 0.15µl/hr, 6µg/day) into the IVth ventricle or basal forebrain cannula tract

  5. Regional microglia activation LPS 21 days → activated microglia in the hippocampus and temporal lobe. 2 Days aCSF + Sal, 4 weeks 21 Days LPS + Sal, 4 weeks

  6. 9 8 7 * 6 * 5 Total Number of Neurons (x104) 4 3 2 1 0 LPS aCSF Is there a pathological consequence? Fewer cresyl violet stained cells counted by stereology in entorhinal cortex layers II and III of rats infused with LPS for 37 days Hauss-Wegrzyniak et al., 2002

  7. Is there a pathological consequence? Volumetric MRI analysis revealed that 42 days of LPS infusion caused a significant shrinkage of the temporal lobes and hippocampus and increase in the volume of the lateral ventricles. aCSF LPS Hauss-Wegrzyniak et al., 2000

  8. Is there a functional consequence? Impaired LTP induction in vivo in dentate gyrus of rats infused with LPS for 37 days Hauss-Wegrzyniak et al., 2002

  9. What underlies a loss of LTP? Glutamate is necessary for LTP Glutamate dysfunction disrupts LTP Glutamate → NMDAR activation → Ca++ entry → Arc induction Mg+ Glutamatergic neuron Ca++ Arc 5 min 30 min Arc in DG Rosi et al., 2005

  10. Chronic neuroinflammation activates microglia (blue) and over-activates Arc (red) a-CSF Arc + hippocampal neurons: aCSF: ~2% LPS: ~4% LPS Rosi et al., 2005

  11. What other regions are vulnerable to chronic neuroinflammation? LPS infused into the nucleus basalis magnocellularis (14, 37, 74 or 112 days) produced a time-dependent, but not dose-dependent, decline in the number of Choline acetyltransferase (ChAT)-immunoreactive cells. Willard et al., 1999

  12. SN dopaminergic neurons are also vulnerable to chronic inflammation LPS + Sal aCSF + Sal a b

  13. Does Gender influence the response to neuroinflammation? Female rats infused 42 days with LPS have ~1/2 the number of activated microglia as males. Estrogen replacement did not protect. ‡ 1600 ‡ 1400 1200 1000 + # Number of Activated Microglia 800 600 400 200 0 aCSF LPS aCSF LPS aCSF LPS OVX OVX + Estrogen Intact Marriott et al., 2002

  14. Microglia activation correlates with impaired water maze performance (r = 0.481, p<0.03) Neuroinflammation did not impair the performance of intact females 1200 1000 800 Path Length (cm) 600 aCSF OVX LPS 400 aCSF 200 Mean + SEM 0 1 2 3 4 Day of Testing Marriott et al., 2002

  15. In the absence of ovaries: • Chronic neuroinflammation impaired performance. • Chronic estrogen impaired performance. • Together, ovariectomy and LPS were synergistic. 1200 1000 + LPS OVX + E2 LPS OVX 800 Path Length (cm) aCSF OVX + E2 * 600 aCSF OVX LPS 400 aCSF 200 Mean + SEM 0 1 2 3 4 Day of Testing Marriott et al., 2002

  16. Regional and cellular vulnerability is influenced by neuroinflammation, time and gender. • Distribution of activated microglia changes over time and concentrates within regions prone to neurodegeneration. • The loss of forebrain acetylcholine neurons and is time-dependent. • Chronic neuroinflammation is likely responsible for the selective vulnerability of specific neural systems and brain regions associated with age-related neurodegenerative changes. • Female rats show no neuroinflammation-induced cognitive impairment unless ovarian function is lost.

  17. Dr. Beatrice Hauss-Wegrzyniak Dr. Susanna Rosi Dr. Gary L. Wenk Holly M. Brothers ICAD 2009 Dr. Lisa Marriott Dr. Yannick Marchalant Supported by NIA Contact: Brothers.23@osu.edu

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