A role for T cells in the induction of memory deficit in mice with Alzheimer’s-like disease

Alzheimer’s disease (AD) is a neurodegenerative disorder representing the most common cause of dementia worldwide. Neuropathological hallmarks of the disease mainly include extracellular beta amyloid deposition and the formation of neurofibrillary tangles composed by hyperphosphorylated tau protein. In addition, studies conducted in AD patients and in AD-like mice models have demonstrated that vascular inflammation and a dysfunctional blood-brain-barrier (BBB) have been implicated in the pathogenesis of AD and T-lymphocytes emerged as pivotal players in inflammatory events exacerbating neuronal damages in AD brain . Since the role played by CD4+ and CD8+ T cell in AD is still debated, we decided to investigate with different approaches the contribution of these cells to disease pathogenesis in a murine model of AD (3xTg-AD mice) that display both Aβ and tau-pathology. At first, we evaluated by flow cytometry the accumulation profile of T cells at different disease stages in the brain of 3xTg-AD mice in comparison to wild-type (WT) mice. We observed that 3xTg-AD mice devoid from CD4+ and CD8+ showed a significant restoration of memory when compared to control animals. Additionally, immunohistochemical studies showed that CD4+ and CD8+ depletion reduce microglia activation and Aβ deposition in cortical and hippocampal regions, the most vulnerable areas during AD progression. Of note, only 3xTg-AD mice devoid of CD8+ T cells displayed a significant reduction of tau phosphorylation, suggesting an association between NFT formation and CD8+ T lymphocytes. Next, we decided to investigate the integrin mediated mechanisms used by T cell to migrate into the brain during AD. We observed that VLA-4 was more abundant on circulating CD4+ T cells. Whereas, examining LFA-1 occurrence on peripheral T cells from 3xTg-AD mice we found the presence of a distinct population highly expressing LFA-1 (LFA-1high) which correlate with the disease progression. Thus, we decided to target VLA-4 and LFA-1 using pharmacological or genetic approaches respectively. Our results showed that the blockade of VLA-4 and LFA-1 improved the memory functions in 3xTg-AD mice compared to controls. Additionally, we observed a reduction of neuropathological hallmarks of AD, including microgliosis, Aβ load and tau hyperphosphorylation. Based on our in vivo evidences we decided to further investigate their interaction with intraparenchymal brain cells using an AD in vitro culture system. We started to develop our model using neuronal cells isolated from the brain of 3xTg-AD mice and WT controls. Firstly, we demonstrated which cells in culture were able to recapitulate AD hallmarks. Once confirmed the powerful characteristics of our in vitro AD-model, we decided to evaluate the effect of Th1 and Th17 cells producing IFN-γ and IL-17 respectively on astrocytes and microglia obtained from 3xTg-AD mice or WT mice. The co-culture was maintained for 24 hours. The flow-cytometry analysis showed that the-coculture with Th1 enhanced the up regulation of CD68, as classical marker of microglia activation. Moreover, microglia kept in the same co-culture condition with Th1 or Th17 cells displayed a higher MHCII expression level compared to control. Additionally, Th1 but not Th17 cells were also able to induce the formation of a more reactivate form of astrocytes, showed by the upregulation of the frequency of CD44+ cells. Overall, the data collected in 3xTg-AD mice and the ones obtained with the use of the in vitro system significantly contributed to the characterization of intravascular and intraparenchymal behaviours of CD4+ and CD8+ T subtypes, suggesting a detrimental role for T lymphocytes that might contribute to disease pathogenesis in AD.