Rahasson R. Ager

The Role of the Anaphylatoxins in Health and Disease

The anaphylatoxin (AT) C3a, C5a and C5a-desArg are generally considered pro-inflammatory polypeptides generated after proteolytic cleavage of C3 and C5 in response to complement activation. Their well-appreciated effector functions include chemotaxis and activation of granulocytes, mast cells and macrophages. Recent evidence suggests that ATs are also generated locally within tissues by pathogen-, cell-, or contact system-derived proteases. This local generation of ATs is important for their pleiotropic biologic effects beyond inflammation. The ATs exert most of the biologic activities through ligation of three cognate receptors, i.e. the C3a receptor, the C5a receptor and the C5a receptor-like, C5L2. Here, we will discuss recent findings suggesting that ATs regulate cell apoptosis, lipid metabolism as well as innate and adaptive immune responses through their impact on antigen-presenting cells and T cells. As we will outline, such regulatory functions of ATs and their receptors play important roles in the pathogenesis of allergy, autoimmunity, neurodegenerative diseases, cancer and infections with intracellular pathogens.

Treatment with a C5aR Antagonist Decreases Pathology and Enhances Behavioral Performance in Murine Models of Alzheimer’s Disease

Alzheimer’s disease (AD) is an age-related dementia, characterized by amyloid plaques, neurofibrillary tangles, neuroinflammation, and neuronal loss in the brain. Components of the complement system, known to produce a local inflammatory reaction, are associated with the plaques and tangles in AD brain, and thus a role for complement-mediated inflammation in the acceleration or progression of disease has been proposed. A complement activation product, C5a, is known to recruit and activate microglia and astrocytes in vitro by activation of a G protein-coupled cell-surface C5aR. Here, oral delivery of a cyclic hexapeptide C5a receptor antagonist (PMX205) for 2–3 mo resulted in substantial reduction of pathological markers such as fibrillar amyloid deposits (49–62%) and activated glia (42–68%) in two mouse models of AD. The reduction in pathology was correlated with improvements in a passive avoidance behavioral task in Tg2576 mice. In 3xTg mice, PMX205 also significantly reduced hyperphosphorylated tau (69%). These data provide the first evidence that inhibition of a proinflammatory receptor-mediated function of the complement cascade (i.e., C5aR) can interfere with neuroinflammation and neurodegeneration in AD rodent models, suggesting a novel therapeutic target for reducing pathology and improving cognitive function in human AD patients.

The Role of the Complement System and the Activation Fragment C5a in the Central Nervous System

The complement system is a pivotal component of the innate immune system which protects the host from infection and injury. Complement proteins can be induced in all cell types within the central nervous system (CNS), where the pathway seems to play similar roles in host defense. Complement activation produces the C5 cleavage fragment C5a, a potent inflammatory mediator, which recruits and activates immune cells. The primary cellular receptor for C5a, the C5a receptor (CD88), has been reported to be on all CNS cells, including neurons and glia, suggesting a functional role for C5a in the CNS. A second receptor for C5a, the C5a-like receptor 2 (C5L2), is also expressed on these cells; however, little is currently known about its potential role in the CNS. The potent immune and inflammatory actions of complement activation are necessary for host defense. However, if over-activated, or left unchecked it promotes tissue injury and contributes to brain disease pathology. Thus, complement activation, and subsequent C5a generation, is thought to play a significant role in the progression of CNS disease. Paradoxically, complement may also exert a neuroprotective role in these diseases by aiding in the elimination of aggregated and toxic proteins and debris which are a principal hallmark of many of these diseases. This review will discuss the expression and known roles for complement in the CNS, with a particular focus on the pro-inflammatory end-product, C5a. The possible overarching role for C5a in diseases of the CNS is reviewed, and the therapeutic potential of blocking C5a/CD88 interaction is evaluated.

Microglial C5aR (CD88) expression correlates with amyloid-β deposition in murine models of Alzheimer’s disease

J. Neurochem. (2010) 113, 389–401.

Short‐term modern life‐like stress exacerbates Aβ‐pathology and synapse loss in 3xTg‐AD mice

Alzheimers disease (AD) is a progressive neurological disorder that impairs memory and other cognitive functions in the elderly. The social and financial impacts of AD are overwhelming and are escalating exponentially as a result of population aging. Therefore, identifying AD‐related risk factors and the development of more efficacious therapeutic approaches are critical to cure this neurological disorder. Current epidemiological evidence indicates that life experiences, including chronic stress, are a risk for AD. However, it is unknown if short‐term stress, lasting for hours, influences the onset or progression of AD. Here, we determined the effect of short‐term, multi‐modal ‘modern life‐like’ stress on AD pathogenesis and synaptic plasticity in mice bearing three AD mutations (the 3xTg‐AD mouse model). We found that combined emotional and physical stress lasting 5 h severely impaired memory in wild‐type mice and tended to impact it in already low‐performing 3xTg‐AD mice. This stress reduced the number of synapse‐bearing dendritic spines in 3xTg‐AD mice and increased Aβ levels by augmenting AβPP processing. Thus, short‐term stress simulating modern‐life conditions may exacerbate cognitive deficits in preclinical AD by accelerating amyloid pathology and reducing synapse numbers.

p-Tau immunotherapy reduces soluble and insoluble tau in aged 3xTg-AD mice

Alzheimers disease (AD) is a proteinopathy characterized by the accumulation of β-amyloid (Aβ) and tau. To date, clinical trials indicate that Aβ immunotherapy does not improve cognition. Consequently, it is critical to modulate other aspects of AD pathology. As such, tau represents an excellent target, as its accumulation better correlates with cognitive impairment. To determine the effectiveness of targeting pathological tau, with Aβ pathology present, we administered a single injection of AT8, or control antibody, into the hippocampus of aged 3xTg-AD mice. Extensive data indicates that phosphorylated Ser(202) and Thr(205) sites of tau (corresponding to the AT8 epitope) represent a pathologically relevant target for AD. We report that immunization with AT8 reduced somatodendritic tau load, p-tau immunoreactivity, and silver stained positive neurons, without affecting Aβ pathology. We also discovered that tau pathology soon reemerges post-injection, possibly due to persistent Aβ pathology. These studies provide evidence that targeting p-tau may represent an effective treatment strategy: potentially in conjunction with Aβ immunotherapy.

Restoration of lipoxin A4 signaling reduces Alzheimer's disease-like pathology in the 3xTg-AD mouse model

The initiation of an inflammatory response is critical to the survival of an organism. However, when inflammation fails to reach resolution, a chronic inflammatory state may occur, potentially leading to bystander tissue damage. Accumulating evidence suggests that chronic inflammation contributes to the progression of Alzheimers disease (AD), and identifying mechanisms to resolve the pro-inflammatory environment stimulated by AD pathology remains an area of active investigation. Previously, we found that treatment with the pro-resolving mediator aspirin-triggered lipoxin A4 (ATL), improved cognition, reduced Aβ levels, and enhanced microglia phagocytic activity in Tg2576 transgenic AD mice. Here, we evaluated the effect of aging on brain lipoxin A4 (LXA4) levels using non-transgenic and 3xTg-AD mice. Additionally, we investigated the effect of ATL treatment on tau pathology in 3xTg-AD mice. We found that LXA4 levels are reduced with age, a pattern significantly more impacted in 3xTg-AD mice. Moreover, ATL delivery enhanced the cognitive performance of 3xTg-AD mice and reduced Aβ levels, as well as decreased the levels of phosphorylated-tau (p-tau). The decrease in p-tau was due in part to an inhibition of the tau kinases GSK-3β and p38 MAPK. In addition, microglial and astrocyte reactivity was inhibited by ATL treatment. Our results suggest that the inability to resolve the immune response during aging might be an important feature that contributes to AD pathology and cognitive deficits. Furthermore, we demonstrate that activation of LXA4 signaling could serve as a potential therapeutic target for AD-related inflammation and cognitive dysfunction.

Diabetes and Alzheimer’s disease crosstalk

Despite intensive research efforts over the past few decades, the mechanisms underlying the etiology of sporadic Alzheimers disease (AD) remain unknown. This fact is of major concern because the number of patients affected by this medical condition is increasing exponentially and the existing treatments are only palliative in nature and offer no disease modifying affects. Interestingly, recent epidemiological studies indicate that diabetes significantly increases the risk of developing AD, suggesting that diabetes may play a causative role in the development of AD pathogenesis. Therefore, elucidating the molecular interactions between diabetes and AD is of critical significance because it might offer a novel approach to identifying mechanisms that may modulate the onset and progression of sporadic AD cases. This review highlights the involvement of several novels pathological molecular mechanisms induced by diabetes that increase AD pathogenesis. Furthermore, we discuss novel findings in animal model and clinical studies involving the use of anti-diabetic compounds as promising therapeutics for AD.

Repeated cognitive stimulation alleviates memory impairments in an Alzheimer's disease mouse model

Alzheimers disease is a neurodegenerative disease associated with progressive memory and cognitive decline. Previous studies have identified the benefits of cognitive enrichment on reducing disease pathology. Additionally, epidemiological and clinical data suggest that repeated exercise, and cognitive and social enrichment, can improve and/or delay the cognitive deficiencies associated with aging and neurodegenerative diseases. In the present study, 3xTg-AD mice were exposed to a rigorous training routine beginning at 3 months of age, which consisted of repeated training in the Morris water maze spatial recognition task every 3 months, ending at 18 months of age. At the conclusion of the final Morris water maze training session, animals subsequently underwent testing in another hippocampus-dependent spatial task, the Barnes maze task, and on the more cortical-dependent novel object recognition memory task. Our data show that periodic cognitive enrichment throughout aging, via multiple learning episodes in the Morris water maze task, can improve the memory performance of aged 3xTg-AD mice in a separate spatial recognition task, and in a preference memory task, when compared to naïve aged matched 3xTg-AD mice. Furthermore, we observed that the cognitive enrichment properties of Morris water maze exposer, was detectable in repeatedly trained animals as early as 6 months of age. These findings suggest early repeated cognitive enrichment can mitigate the diverse cognitive deficits observed in Alzheimers disease.

Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease

Alzheimers disease (AD) is a devastating neurodegenerative disorder that impairs memory and causes cognitive and psychiatric deficits. New evidences indicate that AD is conceptualized as a disease of synaptic failure, although the molecular and cellular mechanisms underlying these defects remain to be elucidated. Determining the timing and nature of the early synaptic deficits is critical for understanding the progression of the disease and for identifying effective targets for therapeutic intervention. Using single‐synapse functional and morphological analyses, we find that AMPA signaling, which mediates fast glutamatergic synaptic transmission in the central nervous system (CNS), is compromised early in the disease course in an AD mouse model. The decline in AMPA signaling is associated with changes in actin cytoskeleton integrity, which alters the number and the structure of dendritic spines. AMPA dysfunction and spine alteration correlate with the presence of soluble but not insoluble Aβ and tau species. In particular, we demonstrate that these synaptic impairments can be mitigated by Aβ immunotherapy. Together, our data suggest that alterations in AMPA signaling and cytoskeletal processes occur early in AD. Most important, these deficits are prevented by Aβ immunotherapy, suggesting that existing therapies, if administered earlier, could confer functional benefits.