Immune Activation in Brain Aging and Neurodegeneration: Too Much or Too Little?

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
Neuron (Impact Factor: 15.05). 10/2009; 64(1):110-22. DOI: 10.1016/j.neuron.2009.08.039
Source: PubMed


Until recently, the brain was studied almost exclusively by neuroscientists and the immune system by immunologists, fuelling the notion that these systems represented two isolated entities. However, as more data suggest an important role of the immune system in regulating the progression of brain aging and neurodegenerative disease, it has become clear that the crosstalk between these systems can no longer be ignored and a new interdisciplinary approach is necessary. A central question that emerges is whether immune and inflammatory pathways become hyperactivated with age and promote degeneration or whether insufficient immune responses, which fail to cope with age-related stress, may contribute to disease. We try to explore here the consequences of gain versus loss of function with an emphasis on microglia as sensors and effectors of immune function in the brain, and we discuss the potential role of the peripheral environment in neurodegenerative diseases.

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Available from: Kurt Lucin, Sep 01, 2014
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    • "Cerebral inflammation occurs through the activation of microglia and recruited peripheral macrophages, and both may promote neurotoxicity and participate in the progression of neurodegeneration [33]. Amyloid-beta aggregates and neurofibrillary tangle can generate an innate immune system response in AD; for this reason, neuroinflammation is considered an important player in the pathogenesis of AD [34]. Interestingly , PPARí µí»¾ activation has been shown to have a potent antiinflammatory effect [35]. "
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    ABSTRACT: Alzheimer’s disease (AD) is a multifactorial metabolic brain disorder characterized by protein aggregates, synaptic failure, and cognitive impairment. In the AD brain is common to observe the accumulation of senile plaques formed by amyloid-beta (A β ) peptide and the neurofibrillary tangles composed of modified tau protein, which both lead to cellular damage and progressive neurodegeneration. Currently, there is no effective therapy for AD; however several studies have shown that the treatments with the peroxisome proliferators activated receptor-gamma (PPAR γ ) agonists known as thiazolidinedione drugs (TZDs), like rosiglitazone and pioglitazone, attenuate neurodegeneration and improve cognition in mouse models and patients with mild-to-moderate AD. Furthermore, studies on animal models have shown that TZDs inhibit neuroinflammation, facilitate amyloid- β plaque clearance, enhance mitochondrial function, improve synaptic plasticity, and, more recently, attenuate tau hyperphosphorylation. How TZDs may improve or reduce these pathologic signs of AD and what the mechanisms and the implicated pathways in which these drugs work are are questions that remain to be answered. However, in this review, we will discuss several cellular targets, in which TZDs can be acting against the neurodegeneration.
    PPAR Research 09/2015; 2015. DOI:10.1155/2015/957248 · 1.64 Impact Factor
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    • "β2AR is the predominant type of adrenergic receptor expressed on B and T lymphocytes in the spleen. NE spike causes lethal overstimulation of β2AR on splenic lymphocytes, and circulating GCs synergize with NE to induce apoptotic signaling in these cells (Lucin et al., 2007, 2009). "
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    ABSTRACT: During the transition from acute to chronic stages of recovery after spinal cord injury (SCI), there is an evolving state of immunologic dysfunction that exacerbates the problems associated with the more clinically obvious neurologic deficits. Since injury directly affects cells embedded within the "immune privileged/specialized" milieu of the spinal cord, maladaptive or inefficient responses are likely to occur. Collectively, these responses qualify as part of the continuum of "SCI disease" and are important therapeutic targets to improve neural repair and neurological outcome. Generic immune suppressive therapies have been largely unsuccessful, mostly because inflammation and immunity exert both beneficial (plasticity enhancing) and detrimental (e.g. glia- and neurodegenerative; secondary damage) effects and these functions change over time. Moreover, "compartimentalized" investigations, limited to only intraspinal inflammation and associated cellular or molecular changes in the spinal cord, neglect the reality that the structure and function of the CNS are influenced by systemic immune challenges and that the immune system is 'hardwired' into the nervous system. Here, we consider this interplay during the progression from acute to chronic SCI. Specifically, we survey impaired/non-resolving intraspinal inflammation and the paradox of systemic inflammatory responses in the context of ongoing chronic immune suppression and autoimmunity. The concepts of systemic inflammatory response syndrome (SIRS), compensatory anti-inflammatory response syndrome (CARS) and "neurogenic" spinal cord injury-induced immune depression syndrome (SCI-IDS) are discussed as determinants of impaired "host-defense" and trauma-induced autoimmunity.
    Experimental Neurology 08/2014; 258C:121-129. DOI:10.1016/j.expneurol.2014.04.023 · 4.70 Impact Factor
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    • "MSN-like striatally derived cell lines [21] are susceptible to TNF-induced apoptosis in vitro [22], [23], suggesting that increased TNF levels in the striatum could be directly toxic to MSNs through activation of pro-apoptotic signaling pathways. In addition, elevated TNF levels could have an indirect effect on neurons by increasing microglial activation, which can result in increased release of cytotoxic substances [24]–[26]. Given that TNF is upregulated in the serum of HD patients and in HD brains post mortem [9], [10], we hypothesized that it plays a critical role in degeneration of MSNs; therefore, we predicted that DN-TNF might protect MSNs by reducing TNF-dependent toxicity on MSNs or by reducing the overall inflammatory state of the striatum. "
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    ABSTRACT: CNS inflammation is a hallmark of neurodegenerative disease, and recent studies suggest that the inflammatory response may contribute to neuronal demise. In particular, increased tumor necrosis factor (TNF) signaling is implicated in the pathology of both Parkinson's disease (PD) and Alzheimer's disease (AD). We have previously shown that localized gene delivery of dominant negative TNF to the degenerating brain region can limit pathology in animal models of PD and AD. TNF is upregulated in Huntington's disease (HD), like in PD and AD, but it is unknown whether TNF signaling contributes to neuronal degeneration in HD. We used in vivo gene delivery to test whether selective reduction of soluble TNF signaling could attenuate medium spiny neuron (MSN) degeneration in the YAC128 transgenic (TG) mouse model of Huntington's disease (HD). AAV vectors encoding cDNA for dominant-negative tumor necrosis factor (DN-TNF) or GFP (control) were injected into the striatum of young adult wild type WT and YAC128 TG mice and achieved 30-50% target coverage. Expression of dominant negative TNF protein was confirmed immunohistologically and biochemically and was maintained as mice aged to one year, but declined significantly over time. However, the extent of striatal DN-TNF gene transfer achieved in our studies was not sufficient to achieve robust effects on neuroinflammation, rescue degenerating MSNs or improve motor function in treated mice. Our findings suggest that alternative drug delivery strategies should be explored to determine whether greater target coverage by DN-TNF protein might afford some level of neuroprotection against HD-like pathology and/or that soluble TNF signaling may not be the primary driver of striatal neuroinflammation and MSN loss in YAC128 TG mice.
    PLoS ONE 05/2014; 9(5):e96544. DOI:10.1371/journal.pone.0096544 · 3.23 Impact Factor
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