[PMC free content] [PubMed] [Google Scholar] [40] Godbout JP, Chen J, Abraham J, Richwine AF, Berg BM, Kelley KW, Johnson RW (2005) Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system, FASEB J 19, 1329C1331. of microglia and astrocytes. Additionally, proinflammatory and senescent microglia phenotype and brain leukocyte infiltration is present at 12 months of age. Conclusion: In 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, A and tau pathologies, neuroinflammation, and neurodegeneration. These animals represent a promising alternative AD mouse model. and gene mutations in FAD patients highlighted A as a potential pathogenic driver of AD. Transgenic expression of these gene mutations in mice helped determine early-on the significant role of and gene mutations on amyloidogenic process underlying A deposition and plaque formation [1C 3]. Despite the prevalence of A plaque pathology in the APP mouse models, these mice do not develop tangle-like pathology [4]. Findings from various APP mouse models suggest that the A pathology, however severe, is insufficient for generating tangle pathology. AD is a complex disorder with many different abnormal pathological changes that manifest during the aging process. This poses a significant challenge in identifying pathogenic mechanisms in the context of sporadic AD. Furthermore, the commonly used AD model in the field represents the FAD pathogenic mechanism affecting a subset of the 5% of the AD cases while 95% of the AD cases are sporadic with no underlying genetic cause. The presence of various cell cycle markers in postmortem AD brains suggests a potential role of neuronal cell cycle re-entry as a possible nongenetic pathogenic process in AD [5C 15]. The presence of neuronal cell cycle markers in AD prompted us to develop a FICZ mouse model for directly testing the pathogenic role of chronic neuronal cell cycle re-entry in AD. Our conditional transgenic mice express SV40 large T antigen (SV40T) regulated by tetracycline response element (TRE) (TRE-SV40T or TAg mice) [16]. SV40T is usually a powerful oncoprotein that activates the cell cycle by FICZ perturbing the retinoblastoma protein (pRb)- and p53-mediated tumor suppressor pathways [17]. Using the tet-off system, we induced ectopic cell cycle activation in postmitotic neurons via neuronally targeted SV40T expression [16]. This was accomplished by crossing the TAg mice with mice expressing the tetracycline-controlled transactivator (tTA) under the control of CamKinase II(Camk2a) promoter (Camk2a-tTA mice or OFF mice) [18]. When combined with the tet-off gene expression system, SV40T-mediated aberrant cell cycle can be induced in the resulting neuronal cell cycle-re-entry (NCCR) mice by removing doxycycline from the diet post-weaning [16]. Our previously published work demonstrate that SV40T expression in postmitotic neurons increases the brain expression of various cell cycle regulatory proteins and neuronal DNA FST synthesis [16]. Furthermore, we exhibited FICZ that these mice also produce AD-like amyloid and tau pathologies with aging [16]. Importantly, the A and tau pathologies in these animals were generated from endogenous mouse proteins in the absence of FAD mutations. It has also been exhibited that SV40T-mediated forced cell cycle re-entry in primary neuron cultures can promote hyperploidy [19] similar to what has been observed in AD and aged brains [10, 20]. Chronic neuroinflammation is usually thought to be a risk factor for AD [21, 22]. It has been shown that microglia activation is usually observed in the prodromal and preclinical stages of AD [23] and microglia activation is usually positively correlated with tau aggregation and amyloid deposition [24].The role of chronic inflammation in AD is highlighted by identification of as genetic risk factors for sporadic AD [25, 26]. Although these gene mutations by themselves do not produce pathological hallmarks of AD in mice, the presence of these gene mutations modulate A plaque formation and clearance in the APP mice [27C 30]. Thus, a large body of research suggests a significant role of inflammation process in AD. A network analysis.