Arginine Deprivation and Immune Suppression in a Mouse Model of Alzheimer's Disease

Abstract

The pathogenesis of Alzheimer's disease (AD) is a critical unsolved question; and although recent studies have demonstrated a strong association between altered brain immune responses and disease progression, the mechanistic cause of neuronal dysfunction and death is unknown. We have previously described the unique CVN-AD mouse model of AD, in which immune-mediated nitric oxide is lowered to mimic human levels, resulting in a mouse model that demonstrates the cardinal features of AD, including amyloid deposition, hyperphosphorylated and aggregated tau, behavioral changes, and age-dependent hippocampal neuronal loss. Using this mouse model, we studied longitudinal changes in brain immunity in relation to neuronal loss and, contrary to the predominant view that AD pathology is driven by proinflammatory factors, we find that the pathology in CVN-AD mice is driven by local immune suppression. Areas of hippocampal neuronal death are associated with the presence of immunosuppressive CD11c ϩ microglia and extracellular arginase, resulting in arginine catabolism and reduced levels of total brain arginine. Pharmacologic disruption of the arginine utilization pathway by an inhibitor of arginase and ornithine decarboxylase protected the mice from AD-like pathology and significantly decreased CD11c expression. Our findings strongly implicate local immune-mediated amino acid catabolism as a novel and potentially critical mechanism mediating the age-dependent and regional loss of neurons in humans with AD.

The human-specificCASP4gene product contributes to Alzheimer-related synaptic and behavioural deficits

“…In addition, we provided evidence that in human AD brain, CASP4 significantly correlates with expression of IL1B and IL6, while correlation with ARG1 or CHIT1 are moderate or low. Although we found no correlation with iNOS expression, this was not altogether surprising as it has been well documented that human iNOS expression is clearly distinct from the mouse counterpart (63)(64)(65). A previous study showed that infiltrating macrophages recruited to amyloid plaques increased expression of proinflammatory cytokines including IL-1b (23).…”

Getting into the brain: liposome-based strategies for effective drug delivery across the blood–brain barrier

“…[105][106][107][108] More recently, a new potential cause for AD has been found in the behavior of certain immune cells that normally protect the brain instead beginning to consume a vital nutrient: the amino acid arginine. 109 This new discovery has implications not only in a new potential cause of the disease but also as a new strategy for targeting disease.…”

Dissecting the Contribution of Vascular Alterations and Aging to Alzheimer’s Disease

“…An increasing number of studies have reported changes in immune system activity, namely, alterations in lymphocyte and macrophage distribution and activation, production of antibodies against self-proteins, as well as atypical proinflammatory factors [25][26][27]. A recent study showed that the pathogenesis of AD in APPSwDI(+)/(+)mNos2(−/−)(CVN)-AD mice is driven by local immune suppression as areas of hippocampal neuronal death are associated with the presence of immunosuppressive CD11c + microglia and extracellular arginase, resulting in arginine catabolism and reduced levels of total brain arginine [28]. In this study, pharmacologic disruption of the arginine utilization pathway significantly decreased the expression of CD11c and protected from AD-like pathology [28].…”

“…A recent study showed that the pathogenesis of AD in APPSwDI(+)/(+)mNos2(−/−)(CVN)-AD mice is driven by local immune suppression as areas of hippocampal neuronal death are associated with the presence of immunosuppressive CD11c + microglia and extracellular arginase, resulting in arginine catabolism and reduced levels of total brain arginine [28]. In this study, pharmacologic disruption of the arginine utilization pathway significantly decreased the expression of CD11c and protected from AD-like pathology [28]. These results raise the question of whether CNS resident microglia or their myeloid counterparts that cross the BBB [24] are beneficial or have deleterious effects and when would be the best time to intervene in microglia activity during disease development and progression.…”