Mechanisms of Brain Region-Specific Amyloid-beta Deposition

Alzheimer's disease (AD) is the most common cause of dementia. A fundamental feature of AD is brain region-specific deposition of extracellular amyloid plaques principally comprised of the amyloid-β (Aβ) peptide. Using mouse models of cerebral Aβ deposition, we examined molecular, cellular and systems-level mechanisms that regulate brain region-specific Aβ accumulation and aggregation. Parallel studies using in vivo multiphoton microscopy and in vivo microdialysis revealed that modest pharmacological reduction of soluble interstitial fluid (ISF) Aβ levels was associated with a dramatic reduction in amyloid plaque formation and growth. We found that ISF Aβ concentrations in several brain regions of APP transgenic mice prior to the onset of plaque deposition were proportional to the degree of subsequent plaque deposition and with the concentration of lactate, a marker of neuronal activity. Moreover, we found that physiological modulation of endogenous neuronal activity by vibrissal manipulation was sufficient to modulate ISF Aβ levels and amyloid plaque growth dynamics. Using a iii novel optical intrinsic signal imaging approach, we found that bilateral functional connectivity magnitude in APP/PS1 mice prior to plaque deposition was proportional to the amount of regional plaque deposition in aged APP/PS1 mice. Furthermore, we found that bilateral functional connectivity was reduced in normal aging and was markedly exacerbated by Aβ deposition. Together, these data suggest that endogenous neuronal activity and functional connectivity may regulate region-specific Aβ plaque deposition. These data advance our understanding of the mechanisms by which the intrinsic metabolic and functional organization of the brain may contribute to AD pathogenesis. iv Acknowledgements