Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network

AbstractProgranulin (PGRN) is implicated in Alzheimer ’s disease (AD) as well as frontotemporal lobar degeneration. Genetic studies demonstrate an association of the commonGRN rs5848 variant that results in reduced PGRN levels with increased risk for AD. However, the mechanisms by which PGRN reduction from theGRN AD risk variant or mutation exacerbates AD pathophysiology remain ill defined. Here, we show that theGRN AD risk variant has no significant effects on florbetapir positron emission tomographic amyloid imaging and cerebrospinal fluid (CSF) A β levels, whereas it is associated with increased CSF tau levels in human subjects of the Alzheimer’s disease neuroimaging initiative studies. Consistent with the human data, subsequent analyses using the APPswe/PS1ΔE9 (APP/PS1) mouse model of cerebral amyloidosis show that PGRN deficiency has n o exacerbating effects on Aβ pathology. In contrast and unexpectedly, PGRN deficiency significantly reduces diffuse Aβ plaque growth in these APP/PS1 mice. This protective effect is due, at least in part, to enhanced microglial Aβ phagocytosis caused by PGRN deficiency-induced expression of TYROB P network genes (TNG) including an AD risk factorTrem2. PGRN-deficient APP/PS1 mice also exhibit less severe axonal dystrophy and partially improved behavior phenotypes. While PGRN deficiency reduces these amyloidosis-related phenotypes, other neuronal injury mechanisms are increased by loss of PGRN, revealing a multidimensional interacti...
Source: Acta Neuropathologica - Category: Neurology Source Type: research