Brain aging is associated with cognitive decline that is accompanied by progressive inflammation processes in the brain. However, the molecular mechanisms that underlie cognitive deficits arising during aging are largely unknown. Not least because of the increasing ageing population, there is a growing need to develop novel ways to treat or prevent cognitive deficits. It is thought that the balance between pro-aging factors and the activity of the anti-aging defense system determines the speed of aging. In the past, our group identified the endogenous cannabinoid system (ECS) as possible part of this defense system influencing brain aging. Activity of the ECS protects the neurons, is involved in the regulation of glial activity and influences the progression of age-related learning and memory deficits.
Andras Bilkei-Gorzo already showed that mice lacking the cannabinoid receptor 1 (CB1 knockout mice) showed an accelerated age-dependent deficit in learning (Bilkei-Gorzo et al. 2005 and 2010). This deficit is accompanied by a loss of neuronal cells in the hippocampus, a brain region that plays a central role in learning and memory processes. In a very recent study that is now published online in PNAS, Önder Albayram from our lab and colleagues investigated the development of age-related cognitive deficits and the underlying histological, molecular changes in genetic models of reduced endocannabinoid signaling. Aged mice, similar to elderly persons, have difficulties to learn or to adapt to new conditions. In a behavioral test for spatial learning in mice, the animals have to find an escape platform in a water tank. Aged control animals learned slower to localize the platform compared to young ones, and also the onset of this deficit came up earlier in mice lacking CB1 receptors. This memory impairment was accompanied with an enhanced activity of microglia, which are immune cells of the brain. By using a genetic technique that allows the inactivation of the CB1 receptor protein just in a specific type of neurons in the mice, they were able to identify those cells that were responsible for the animals’ poor performance. Thus, only the deletion of the CB1 receptor in GABAergic neurons resulted in a similar cell loss and increased neuroinflammation in the hippocampus as observed in animals lacking the receptors in all cells. Önder Albayram now suggests that activation of CB1 receptors on GABAergic neurons plays an important role in the regulation of microglia cells, which protects against age-related changes in the brain and thus against cognitive deficits.
ORIGINAL RESEARCH PAPER
O. Albayram, J. Alferink, J. Pitsch, A. Piyanova, K. Neitzert, K. Poppensieker, D. Mauer, K. Michel, A. Legler, A. Becker, K. Monory, B. Lutz, A. Zimmer, and A. Bilkei-Gorzo. Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging. PNAS 2011; published ahead of print June 20, 2011, doi:10.1073/pnas.1016442108.
Schizophrenia is a devastating mental disorder with a complex symptomatology that among others comprises hallucinations and delusions (so-called positive symptoms), emotional blunting, poverty of speech, asociality and listlessness (negative symptoms) as well as cognitive dysfunctions. It is known from human genetic studies that, besides environmental factors, there is a strong genetic contribution to disease development. It may at first sight seem weird to study schizophrenia in mice, but mouse models are valuable tools to improve our knowledge for the disease. It is undoubted that we cannot study hallucinations or delusions in mice, but we can certainly get information about their emotional and cognitive state by using specific behavioral tests.
Interestingly, there is only one schizophrenia-associated locus that is not found in rodents: The human G72/G30 gene region. Therefore, David-M. Otte recently generated and characterized a mouse line in our laboratory by introducing the human G72/G30 locus into the mouse genome. These so-called transgenic mice in fact exhibited schizophrenia-like symptoms (Otte et al., 2009). In a follow-up study, David-M. Otte and his collaborators specifically addressed the cognitive impairment observed in the G72 animals. They revealed that the communication between neurons is disturbed, due to dysfunctions in the energy metabolism of the cells. Abnormalities in energy-producing mitochondria lead to oxidative stress, meaning that there is an overproduction of deleterious reactive oxygen species. The poor cognitive abilities of the G72 transgenic mice improved dramatically after feeding them with NAC (N-acetyl cysteine). NAC is a precursor of the tripeptide glutathione, which acts as an antioxidant by scavenging reactive oxygen species. Indeed, NAC treatment led to an increased cognitive performance in the transgenic mice, which suggests an option for the therapy of G72-associated psychiatric disorders like schizophrenia.
ORIGINAL RESEARCH PAPER
Otte DM, Sommersberg B, Kudin A, Guerrero C, Albayram O, Filiou MD, Frisch P, Yilmaz O, Drews E, Turck CW, Bilkei-Gorzó A, Kunz WS, Beck H, Zimmer A. N-acetyl Cysteine Treatment Rescues Cognitive Deficits Induced by Mitochondrial Dysfunction in G72/G30 Transgenic Mice. Neuropsychopharmacology. 2011 Jun 29. doi: 10.1038/npp.2011.109. [Epub ahead of print].
Hope through research: Chemokine receptor 4 controls disease severity in a mouse model for Multiple Sclerosis
Multiple Sclerosis (MS) is a chronic inflammatory disease of the human central nervous system (CNS). During an MS attack, inflammation occurs in areas of the white matter of the CNS in random patches called plaques and is followed by a degradation of myelin sheaths that cover the axons of neurons. This inflammatory process is supposed to be caused by the body’s own immune system that attacks the myelin sheaths, thereby causing disturbances of signal transmission between neurons. As a result, patients suffering from this disease display a variety of symptoms including muscle weakness, vision disorders and paralysis. Judith Alferink and her co-workers now investigated the underlying mechanisms of this disease in a mouse model for MS, the experimental autoimmune encephalomyelitis (EAE). In this model, mice immunized with CNS-derived antigens develop pathological lesions similar to those in MS patients. Their studies revealed a mechanism that leads to an almost complete absence of clinical symptoms in these mice.
The reason for the demyelination of neurons in EAE is a progressive inflammatory response in the CNS mediated by myelin-reactive CD4 T lymphocytes. It is well established that dendritic cells are responsible for the activation of autoreactive CD4 T lymphocytes in peripheral lymphoid tissues, which in turn migrate into the brain and attack the myelin sheaths. However, the mechanisms by which dendritic cells control the disease were yet unclear. Judith Alferink now presented new data in an article in PNAS, showing for the first time that the chemokine receptor 4 (CCR4) on dendritic cells plays a pivotal role in this process by propagating the inflammatory response in the CNS. They were able to define that the production of the protein GM-CSF in dendritic cells is regulated by CCR4 receptors and is required for the development of the disease through modulation of the cytokine IL-23. IL-23 is critically required for the maintenance of autoreactive CD4 T lymphocytes in the CNS. Contrariwise, in genetically modified mice that lack CCR4, the clinical course of disease was strongly alleviated. Based on these new findings, targeting dendritic cell-specific CCR4 signaling pathways is a promising therapeutic approach for the treatment of CNS autoimmunity.
ORIGINAL RESEARCH PAPER
Poppensieker K, Otte DM, Schürmann B, Limmer A, Dresing P, Drews E, Schumak B, Klotz L, Raasch J, Mildner A, Waisman A, Scheu S, Knolle P, Förster I, Prinz M, Maier W, Zimmer A, Alferink J. CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells. PNAS Published online before print February 21, 2012, doi: 10.1073/pnas.1114153109.