Gliosis Precedes Amyloid-β Deposition and Pathological Tau Accumulation in the Neuronal Cell Cycle Re-Entry Mouse Model of Alzheimer's Disease.

backgroundThe presence of cell cycle markers in postmortem Alzheimer's disease (AD) brains suggest a potential role of cell cycle activation in AD. It was shown that cell cycle activation in postmitotic neurons in mice produces Aβ and tau pathologies from endogenous mouse proteins in the absence of AβPP or tau mutations.

objectiveIn this study, we examined the microglial and astrocytic responses in these mice since neuroinflammation is another key pathological feature in AD.

methodsOur neuronal cell cycle re-entry (NCCR) mouse model are bitransgenic mice heterozygous for both Camk2a-tTA and TRE-SV40T. Using this tet-off system, we triggered NCCR in our animals via neuronal expression of SV40T starting at 1 month of age. TRE-SV40T Tg mice were used as SV40T transgene controls. The animals were examined at following time points: 2, 3, 4, 6, and 12 months of age. The microglia and astrocyte responses in our mice were determined by image analysis and stereology on brain sections immunofluorescently labeled using the following antibodies: Iba1, CD45, CD68, MHCII, and GFAP. Cellular senescent marker p16 was also used in this study.

resultsOur NCCR mice demonstrate early and persistent activation of microglia and astrocytes. Additionally, proinflammatory and senescent microglia phenotype and brain leukocyte infiltration is present at 12 months of age.

conclusionIn the absence of FAD gene mutations, our NCCR mice simultaneously display many of the pathological changes associated with AD, such as ectopic neuronal cell cycle re-entry, Aβ and tau pathologies, neuroinflammation, and neurodegeneration. These animals represent a promising alternative AD mouse model.