P1‐492: Identifying region‐specific contributions to entorhinal‐hippocampal network vulnerability in Alzheimer's disease

Why distinct neurodegenerative disorders affect specific neuronal populations is largely unknown. Granule cells of the dentate gyrus are particularly vulnerable to Aβ-induced molecular and functional impairments. Aβ may exert these effects within granule cells, in their immediate extracellular milieu after being released from granule cells or synaptic contacts, or by affecting neurons in distant regions that provide afferent input to granule cells. To identify where Aβ first acts within the entorhinal-hippocampal network to ultimately elicit molecular and behavioral deficits. We engineered lentiviral vectors to express either green fluorescent protein (lenti-GFP) or human amyloid precursor protein (lenti-hAPP) carrying Swedish and London mutations under control of the human ubiquitin C promoter. Wildtype mice received injections of lenti-hAPP into one dentate gyrus (or entorhinal cortex) and of lenti-GFP into the opposite dentate gyrus (or entorhinal cortex) at 2–3 months of age. The distribution and cellular localization of lentivirus-mediated expression of hAPP was analyzed 2 and 6 weeks later by immunohistochemistry, and compared with hAPP transgenic mice from line J20. Six weeks after a single viral injection, hAPP was specifically expressed within the dentate gyrus at high levels throughout the rostral-caudal extent of the hippocampus. Granule neurons represented the clear majority of immunolabeled cells, with little to no labeling of pyramidal neurons in CA regions. Within granule neurons, hAPP was expressed in a punctate pattern that was practically indistinguishable between lentivirus-infected cells and uninfected granule cells from hAPP transgenic mice. In the entorhinal cortex, lentivirus-mediated expression of hAPP was also localized primarily to neurons. Deposition of Aβ into plaques was not detected at these early time points. Ongoing experiments are analyzing the effects of this region-specific neuronal expression of hAPP on molecular alterations previously correlated with behavioral deficits in hAPP transgenic mice. Lentivirus-mediated expression of hAPP/Aβ may be an effective tool with which to probe the source of selective vulnerability within the entorhinal-hippocampal network. Understanding where APP/Aβ first triggers network dysfunction may enable the design of new strategies to better protect the most vulnerable brain regions in AD patients. Supported by NIA grant AG022074.