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 cellular vulnerability in 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. Cagnin et al., 2001 Mutant Proteins Inflammation Synaptic Loss/ Neuronal Death Dementia Symptoms

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

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

6. Is there a pathological consequence? 1 2 3 4 5 6 7 8 9 * Total Number of Neurons (x10 4 ) 0 aCSF LPS * 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. 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. Hauss-Wegrzyniak et al., 2000 Is there a pathological consequence? aCSFLPS

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

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

11. 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 What other regions are vulnerable to chronic neuroinflammation?

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

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

14. Microglia activation correlates with impaired water maze performance ( Microglia activation correlates with impaired water maze performance (r = 0.481, p<0.03) Neuroinflammation did not impair the performance of intact females Day of Testing 1234 Path Length (cm) 0 200 400 600 800 1000 1200 aCSF OVX LPS aCSF Mean+ SEM Marriott et al., 2002

15. In the absence of ovaries: Chronic neuroinflammation impaired performance. Chronic estrogen impaired performance. Together, ovariectomy and LPS were synergistic. Day of Testing 1234 Path Length (cm) 0 200 400 600 800 1000 1200 Mean+ SEM Marriott et al., 2002 + * LPS OVX + E2 LPS OVX aCSF OVX + E2 aCSF OVX LPS aCSF

16. 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. Regional and cellular vulnerability is influenced by neuroinflammation, time and gender.

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