The Effect of Heterozygous Loss of Progranulin on Alzheimer's Disease

Haploinsufficient loss of progranulin (PGRN) is implicated in both frontotemporal lobar dementia (FTD) and Alzheimer’s disease (AD). Furthermore, Grn polymorphisms have been linked to various other neurodegenerative diseases suggesting PGRN plays an important role in neurodegenerative disease pathways. Although genetic studies have demonstrated that partial loss of PGRN increases the risk of AD there are conflicting reports in mouse studies examining the loss of PGRN and it is unclear how the loss of PGRN modulates AD pathophysiology. Therefore, the present study was designed to elucidate the effect of haploinsufficiency loss of PGRN on the pathophysiology of AD. To this end, we characterized a novel PGRN haploinsufficient mouse model (Grn+/-) across age. Utilizing a battery of cognitive and non-cognitive behavior tests we observed key FTD-related behavior deficits in Grn+/- mice across age in the absence of FTD-related pathology including neuroinflammation and TDP-43 proteinopathy as measured by immunohistochemical and western blot techniques. We observed functional deficits in Grn+/- mice, including impaired long-term potentiation and reduced numbers of GABAergic interneurons. Next, we investigated the role of haploinsufficiency PGRN loss on tau pathology by crossing Grn+/- mice with the P301S tau transgenic mouse model. There were slight differences in tau-related non-cognitive behavior deficits and reduced AT8 tau phosphorylation in the brain and spinal cord measured by western blot techniques. While we did not observe differences in microglial activation, we observed alterations in the Akt signaling pathway. Lastly, we investigated the role of haploinsufficiency PGRN loss on amyloid pathology by crossing Grn+/- mice with the APdE9 amyloid transgenic mouse model. We observed exacerbated deficits in AD-related cognitive and non-cognitive behavior, including worsened cognitive learning and memory and motor coordination. We also observed biochemical and morphological changes in amyloid pathology. While we did ...