O4‐08‐08: Progranulin gene therapy prevents plaque formation and synapse loss in a rodent model of AD

Abstract

Progranulin (PGRN) is a multifunctional secreted protein expressed primarily by neurons and microglia. Evidence suggests that PGRN may function as a neurotrophic factor and may be essential for long-term neuronal survival, actively protecting neuronal cells from premature death. It also appears to be important for regulating neuroinflammation, consistent with its localization in microglial cells. Loss-of-function mutations in the PGRN gene have been identified as the cause of some forms of fronto-temporal dementia and mutations in PGRN have also been associated with AD and Lewy Body Dementia. Upregulated expression of PGRN has been reported in numerous neurodegenerative diseases involving microglial activation, including motor neuron disease, lysosomal storage disease, and Alzheimer's disease. In light of its role as a neurotrophic factor, this upregulation may represent an attempt to repair damage and protect cells. Here, we present data describing the effects of ND-602, a proprietary construct designed to target PGRN synthesis. The Tg2576 mouse model of AD expresses the Swedish mutation of APP (APPK67ON,M671L) at high levels under the control of the hamster prion protein promoter. These mice develop a progressive, age-related deposition in the form of amyloid plaques in the cortex and hippocampus. A rapid increase in insoluble Aß occurs around 6 months of age and plaques begin to form around 8-12 months of age, resulting in the development of memory deficits. At 8 months of age, Tg2576 mice received unilateral intracerebral injection of either a progranulin-expressing lentiviral vector (ND-602), or a control vector expressing green fluorescent protein (GFP), into the left dorsal hippocampus. At 12 months of age, animals were sacrificed and the brains assessed for pathology. ND-602 was capable of elevating PGRN expression in the dorsal hippocampus, frontal cortex, and entorhinal cortex. Elevations in PGRN expression were associated with increased neprilysin expression, reduced plaque burden, decreased neuroinflammation, and preservation of synapses. Together, the data reported here indicate that ND-602 treatment regulates Aß, a key causal factor in AD, by reducing tissue levels in Tg2576 mice as well as plaque deposition. Thus, ND-602, by targeting PGRN, may represent a potential therapy designed to slow or halt disease progression in AD. Hippocampal β-amyloid burden following lentiviral delivery. (A) Representative photomicrographs depicting β-amyloid immunolabeling in the hippocampal dentate gyrus of a Tg2576 mouse brain 6 months following unilateral intracerebral administration of either LV-GFP, or LV-PGRN (ND-602). (B) Amyloid burden was significantly reduced in the ipsilateral dentate gyrus of those animals receiving ND-602 administration. Each bar represents the mean (± S.E.M.) (n = 10) amyloid burden (% area) measured across 4 coronal sections. ∗∗ sig. diff. from GFP-treated controls, p<0.001.