P2‐091: SV40T‐MEDIATED NEURONAL CELL CYCLE DYSREGULATION IN MICE INDUCES Aβ AND TAU PATHOLOGIES AND NEUROINFLAMMATION

Abstract

The majority of the Alzheimer's disease (AD) cases are sporadic and generate Aβ plaques and neurofibrillary tangles in the absence of mutations in the APP or tau proteins. The presence of cell cycle markers in postmortem AD brains has led a number of researchers to suggest a potential role of cell cycle activation in AD. My previously published findings demonstrated that cell cycle induction in postmitotic neurons in mice produces Aβ and tau pathologies in the absence of APP or tau mutations (Park et al., 2007, J Neurosci). Our recent work examines the microglial and astrocytic responses in these mice. SV40T expression was restricted to postmitotic neurons in our mice using the tet-off system. Our inducible transgenic mice express SV40T under the regulation of TRE promoter (Tag mice). Tag mice were paired with Camk2a-tTA transgenic mice (Off mice) and maintained on doxycycline (dox) diet. The offspring were maintained on dox diet until 30 days of age, at which point they were continuously maintained on standard diet. Tag mice were used as SV40T transgene controls. Animals were examined at 2, 4, 6, and 12 months of age. Vibratome sectioned brains were immunofluorescent labeled for Iba1, CD45, CD68, MHCII and GFAP. Cellular senescence was assessed using anti-p16 antibody. Microglia and astrocyte activations are observed as early as 2 months of age after neuronal cell cycle activation. Tag/Off mice demonstrated increase in GFAP immunolabeling compared to Tag mice, indicative of astrocyte activation. Tag/Off mice also showed increased Iba1 immunostaining compared to Tag mice. A subset of Iba1-positive microglia showed co-labeling with CD45, CD68, or MHCII antibodies, demonstrating activated microglia. At 12-months of age, microglia demonstrates blebbing and p16 immunopositivity, both hallmarks of senescent phenotype. Our Tag/Off mice demonstrate early and persistent activation of microglia and astrocytes. Additionally, these mice develop senescent microglia phenotype along with Aβ and tau pathologies following chronic and persistent neuronal cell cycle activation. Our mice simultaneously display the major pathological features of AD in the absence of APP or tau mutations, and thereby may represent a sporadic AD mouse model.