Article

How to Get from Here to There: Macrophage Recruitment in Alzheimer's Disease

Regenerative Medicine Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Blvd., SSB3 Room 361, Los Angeles, CA 90048, USA.
Current Alzheimer research (Impact Factor: 3.8). 02/2011; 8(2):156-63. DOI: 10.2174/156720511795256017
Source: PubMed

ABSTRACT Alzheimer's disease (AD) is pathologically defined by presence of intracellular neurofibrillary tangles and extracellular amyloid plaques comprised of amyoid-β (Aβ) peptides. Despite local recruitment of brain microglia to sites of amyloid deposition, these mononuclear phagocytes ultimately fail at restricting β-amyloid plaque formation. On the other hand, it is becoming increasingly clear that professional phagocytes from the periphery possess Aβ clearance aptitude. Yet, in order to harness this beneficial innate immune response, effective strategies must be developed to coax monocytes/macrophages from the periphery into the brain. It has previously been suggested that Aβ 'immunotherapy' clears cerebral Aβ deposits via mononuclear phagocytes, and recent evidence suggests that targeting transforming growth factor-β-Smad 2/3 signaling and chemokine pathways such as Ccr2 impacts blood-to-brain trafficking of these cells in transgenic mouse models of AD. It has also been shown that the fractalkine receptor (Cx3cr1) pathway plays a critical role in chemotaxis of mononuclear phagocytes toward neurons destined for death in AD model mice. In order to translate these basic science findings into AD treatments, a key challenge will be to develop a new generation of pharmacotherapeutics that safely and effectively promote recruitment of peripheral amyloid phagocytes into the AD brain.

Download full-text

Full-text

Available from: David Gate, Aug 13, 2014
0 Followers
 · 
143 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Blood transcriptome has emerged as a potential resource for the discovery of biomarkers for Alzheimer's disease (AD). However, the validity of blood transcriptome in the early diagnosis of AD has yet to be extensively tested. In this work, we analyzed published data on AD blood transcriptome and revealed the characteristic perturbation of cellular functional units, including upregulation of environmental responses (immune response, survival/death signaling, and cellular recycling) and down-regulation of core metabolism (energy metabolism and translation/splicing). This characteristic perturbation was unique to AD based on the comparison with blood transcriptome from other neurological disorders and complex diseases. More importantly, similar perturbation was observed in both AD and mild cognitive impairment (MCI) groups. This perturbation pattern was further validated in our independent microarray experiment in a small Chinese cohort. In addition, the potential effect of aging and lifestyle on blood transcriptome was discussed. Based on the analyses, we propose that the transformation of the blood transcriptome in AD is an integrated part of the disease mechanism and has potential to serve as a reliable biomarker for assisting the early diagnosis as well as monitoring purpose. Therefore, more independent studies on blood transcriptome of AD and MCI with larger sample size are warranted.
    Journal of Alzheimer's disease: JAD 02/2013; 35(2). DOI:10.3233/JAD-121963 · 3.61 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The role of inflammation in neurodegenerative diseases has been widely demonstrated. Intraneuronal protein accumulation may regulate microglial activity via the fractalkine (CX3CL1) signaling pathway that provides a mechanism through which neurons communicate with microglia. CX3CL1 levels fluctuate in different stages of neurodegenerative diseases and in various animal models, warranting further investigation of the mechanisms underlying microglial response to pathogenic proteins, including Tau, β-amyloid (Aβ), and α-synuclein. The temporal relationship between microglial activity and localization of pathogenic proteins (intra- versus extracellular) likely determines whether neuroinflammation mitigates or exacerbates disease progression. Evidence in transgenic models suggests a beneficial effect of microglial activity on clearance of proteins like Aβ and a detrimental effect on Tau modification, but the role of CX3CL1 signaling in α-synucleinopathies is less clear. Here we review the nature of fractalkine-mediated neuronmicroglia interaction, which has significant implications for the efficacy of anti-inflammatory treatments during different stages of neurodegenerative pathology. Specifically, it is likely that anti-inflammatory treatment in early stages of disease during intraneuronal accumulation of proteins could be beneficial, while anti-inflammatory treatment in later stages when proteins are secreted to the extracellular space could exacerbate disease progression.
    08/2012; 2012:345472. DOI:10.1155/2012/345472
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We evaluated the therapeutic efficacy of combined treatment of Aβ-immunization with simvastatin in an Alzheimer mouse model at age 22 months. DNA prime-adenovirus boost immunization induced modest anti-Aβ titers and simvastatin increased the seropositive rate. Aβ-KLH was additionally administered to boost the titers. Irrespective of simvastatin, the immunization did not decrease cerebral Aβ deposits but increased soluble Aβ and tended to exacerbate amyloid angiopathy in the hippocampus. The immunization increased cerebral invasion of leukocytes and simvastatin counteracted the increase. Thus, modest anti-Aβ titers can increase soluble Aβ and simvastatin may reduce inflammation associated with vaccination in aged Alzheimer mouse models.
    Journal of neuroimmunology 03/2012; 244(1-2):70-83. DOI:10.1016/j.jneuroim.2012.01.008 · 2.79 Impact Factor