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

Abstract

Background: The 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. Objective: In this study, we examined the microglial and astrocytic responses in these mice since neuroinflammation is another key pathological feature in AD. Methods: Our 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. Results: Our 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. 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, Aβ and tau pathologies, neuroinflammation, and neurodegeneration. These animals represent a promising alternative AD mouse model.

E2F4-Based Gene Therapy Mitigates the Phenotype of the Alzheimer's Disease Mouse Model 5xFAD

“…Forced cell cycle re-entry in neurons results in classical hallmarks of AD, including tau protein hyperphosphorylation and neurofibrillary tangles (NFT), increased APP processing and extracellular deposits of Aβ, neuronal cell death, gliosis, and cognitive deficits [69][70][71][72], and it has been shown to enhance the phenotype of a murine model of AD [73]. Musi et al [74] have recently shown that genes involved in cell cycle progression are upregulated in human NFTcontaining neurons.…”

Design and Synthesis of New Benzo[d]oxazole-Based Derivatives and Their Neuroprotective Effects on β-Amyloid-Induced PC12 Cells

“…Tau is the major neuronal microtubule associated protein. In the brain of AD patients, tau is abnormally hyperphosphorylated, accumulating as intraneuronal tangles and failing to maintain structures [ 43 ], causing cell apoptosis [ 44 , 45 , 46 ]. Thus, pharmacologic strategies designed to suppress hyperphosphorylation of tau may be beneficial for the treatment of AD.…”

Neuronal Cell Cycle Re-Entry Enhances Neuropathological Features in AppNLF Knock-In Mice

“…The relationship between neuronal cell cycle re-entry and various AD pathologies has been demonstrated in various models. Connections have been made between neuronal cell cycle re-entry and A␤ pathology [25,32], tau dysfunction [25,[33][34][35], neuroinflammation [24,26,36,37], and neuronal loss [24,25,33]. Of these models, our Simian Virus 40 Large T (SV40T)-mediated neuronal cell cycle re-entry mouse model is the only one shown to simultaneously display the greatest number of pathologies associated with AD [24,26].…”

“…The expression of SV40T is targeted to excitatory forebrain neurons by crossing the TAg mice with Camk2a-tTA Tg mice that express tetracycline-controlled transactivator (tTA) under the control of the CamKinase II␣ (Camk2a) promoter (Camk2a-tTA, or "OFF" mice) [50]. Mice expressing both "TAg" and "OFF" undergo neuronal cell cycle re-entry once doxycycline is removed from the diet, typically at one month of age [25,37]. And this neuronal cell cycle re-entry is abolished when the animals are put back on dox diet to suppress SV40T expression [37].…”

“…Mice expressing both "TAg" and "OFF" undergo neuronal cell cycle re-entry once doxycycline is removed from the diet, typically at one month of age [25,37]. And this neuronal cell cycle re-entry is abolished when the animals are put back on dox diet to suppress SV40T expression [37]. Our work using the TAg (het)/OFF (het) bi-transgenic mice (hereafter referred to as neuronal cell cycle re-entry (NCCR) mice) showed that forced ectopic neuronal cell cycle activation induces a number of pathological features that mirror multiple pathological hallmarks of AD: A␤ and tau pathologies from endogenous mouse proteins, gliosis, neuroinflammation, brain leukocyte infiltration, and neurodegeneration [25,37].…”