This study suggests that immune responses in the CNS may be involved in the transition to AD dementia. Our goal was to identify factors which correlate with cognitive decline by comparing non-demented controls, including high-pathology controls, to cases with mild/moderate clinical grades of AD dementia. We demonstrated that inflammatory molecules, most prominently MHC II, a marker of microglia activation, were increased in AD patients with early stage dementia. One prominent consequence of MHC II up-regulation is the potential for antigen presentation to activated T cells thereby inducing an adaptive immune response. However, mild/moderate AD dementia cases had reduced numbers of T cells compared to non-demented controls, suggesting that adaptive immune responses may be dysfunctional during the early stages of AD dementia and may contribute to the cognitive decline observed in these individuals. This work complements a number of prior studies which have also demonstrated immune responses in AD, both in the CNS [2
] and also from peripheral lymphocytes [27
]. However as we have focused on the dementia component of AD, rather than the pathology, we highlight that this immune response may be directly involved in cognitive decline.
In the hippocampus, a primary area implicated in learning and memory, several members of the MHC class II family are significantly increased, in both mRNA and protein levels, at early stages of AD dementia and this increase is inversely correlated with MMSE scores of cognitive function. The comparison with control cases that were cognitively intact but had high AD pathology supports the notion that increased MHC class II levels are correlated to the dementia component of the disease. Previous studies have highlighted abnormal MHC II expression in AD [30
] as well as in transgenic mouse models of AD [18
], which suggests that these effects on MHC II are mediated by increased APP fragments including Aβ. In addition, severe late stage AD dementia has been correlated with increased MHC class II levels in the brain [4
]. The current study provides evidence showing that the increase in MHC class II occurs earlier than previously described, is already present in cases with mild to moderate AD dementia and correlates inversely with MMSE scores.
In addition to increased MHC class II molecules, two other lines of evidence presented here indicate that T cell mediated adaptive immunity may be involved in the transition to AD dementia. First, MHC class II expression was restricted to microglia cells and these cells co-localized with Aβ, suggesting that Aβ may be an antigen being presented. MHC class II expression in activated microglia associated with plaques has been previously established [53
]. Second, the presence of T cells in the hippocampus of mild to moderate AD dementia cases, as well as controls, suggests a potential for a T cell response. Although the central nervous system (CNS) has been thought to be immunologically privileged, T cells have been shown to routinely penetrate the blood brain barrier (BBB) and enter the CNS [23
] and they are present in the aged human hippocampus [63
] as well as the AD brain [25
]. We hypothesize that since in AD patients Aβ can cross the BBB and enter into the bloodstream, it is likely that the immune system can recognize this self-antigen and induce specific immune responses. In support, Monsonego and colleagues demonstrated the presence of Aβ-reactive T cells restricted to MHC class II in the brains of AD patients with moderate to severe grades of dementia [43
]. These Aβ-reactive T cells may have been recruited by microglia, since microglia have been shown to serve as antigen presenting cells that stimulate T cells in vitro
]. However, the exact role of T cells in the AD brain remains ambiguous. This ambiguity stems from evidence that T cells may actually die during inflammatory cascades [17
]. Monsonego and colleagues documented that T cell apoptosis, caused by nitric oxide (NO) production at sites of Aβ plaques [21
], occurs prior to T cell activation by microglia [43
]. In the current study, we show that early stage AD dementia is associated with a decreased number of T cells in the hippocampus as compared to non-demented controls, suggesting that the T cell response in AD is dysfunctional. In addition to T cell death, lack of co-stimulatory molecules is known to induce T cell anergy. In the current study, CD80 and CD86 co-stimulatory molecules are not found to be altered at the mRNA level between non-demented control and mild/moderate dementia cases (data not shown), suggesting that proper activation of cell-mediated immunity is not taking place, although this may be due to the small sample size that T cells constitute in the brain homogenates. Therefore, it is unclear whether the antigen presentation capacity of MHC II-positive microglia cells to T cells in the AD brain is a functional process leading to Aβ removal, or if removal is inhibited by the death and/or anergy of T cells.
Importantly, there is also an established positive link between T cells and cognition. More specifically, T cell deficiency has been associated with deficits in spatial learning and memory [28
]. In addition, a recent study demonstrated that CNS-specific T cells maintain neurogenesis and are required for spatial learning and memory in adulthood [68
]. Immune deficient SCID mice show memory deficits and the addition of CNS-specific T cells restored neurogenesis and improved cognition [68
]. Our studies show a decrease in T cells in AD. Therefore, it is interesting to speculate that decreased T cells contribute to the cognitive deficits observed in transitional AD cases as compared to non-demented controls including individuals with high plaque and/or tangle pathology.
In conclusion, increased microglia activation, paralleled by a decrease in T cell number, correlates with the initial stages of AD dementia. In particular, the progression into AD-type dementia coincides with a specific MHC class II increase in the hippocampus, the primary brain area related to learning and memory. Thus, MHC class II-positive microglia-mediated adaptive immunity may be fundamental to the cognitive decline that occurs in AD. But the findings of decreased T cells in the same brain region suggest that cognitive decline in AD is associated with immune dysfunction.