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: 3.89). 02/2011; 8(2):156-63. DOI: 10.2174/156720511795256017
Source: PubMed


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.

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Available from: David Gate, Aug 13, 2014
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    • "The overexpression of NEP in hematopoetic lineages is therefore concerning. It is also worth noting that without irradiation, concurrent stroke, or additional treatments, very few monocytes appear to migrate into the AD brain [28]. Thus, monocyte mediated delivery of NEP may not provide as robust a therapeutic approach as NSC-based delivery. "
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    ABSTRACT: Introduction Short-term neural stem cell (NSC) transplantation improves cognition in Alzheimer’s disease (AD) transgenic mice by enhancing endogenous synaptic connectivity. However, this approach has no effect on the underlying beta-amyloid (Aβ) and neurofibrillary tangle pathology. Long term efficacy of cell based approaches may therefore require combinatorial approaches. Methods To begin to examine this question we genetically-modified NSCs to stably express and secrete the Aβ-degrading enzyme, neprilysin (sNEP). Next, we studied the effects of sNEP expression in vitro by quantifying Aβ-degrading activity, NSC multipotency markers, and Aβ-induced toxicity. To determine whether sNEP-expressing NSCs can also modulate AD-pathogenesis in vivo, control-modified and sNEP-NSCs were transplanted unilaterally into the hippocampus of two independent and well characterized transgenic models of AD: 3xTg-AD and Thy1-APP mice. After three months, stem cell engraftment, neprilysin expression, and AD pathology were examined. Results Our findings reveal that stem cell-mediated delivery of NEP provides marked and significant reductions in Aβ pathology and increases synaptic density in both 3xTg-AD and Thy1-APP transgenic mice. Remarkably, Aβ plaque loads are reduced not only in the hippocampus and subiculum adjacent to engrafted NSCs, but also within the amygdala and medial septum, areas that receive afferent projections from the engrafted region. Conclusions Taken together, our data suggest that genetically-modified NSCs could provide a powerful combinatorial approach to not only enhance synaptic plasticity but to also target and modify underlying Alzheimer’s disease pathology.
    Full-text · Article · Apr 2014 · Stem Cell Research & Therapy
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    • "The aberrant accumulation of Aβ1-42 is directly involved in the escalation of the neuronal injuries typical of AD [44]–[46], and its plasma levels strictly correlate to the severity of the disease [43], [47]. The self-associating Aβ1-42 peptides form nucleation centers [48] from where the amyloid fibrils can quickly grow, contributing primarily to form the AD-related senile plaques [49]–[54]. The huge tendency of Aβ1-42 to display fibril formation has clearly been demonstrated by in vitro assays [55]. "
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    ABSTRACT: (Aloisi and Barca contributed equally to the work) Carnosine is an endogenous dipeptide abundant in the central nervous system, where by acting as intracellular pH buffering molecule, Zn/Cu ion chelator, antioxidant and anti-crosslinking agent, it exerts a well-recognized multi-protective homeostatic function for neuronal and non-neuronal cells. Carnosine seems to counteract proteotoxicity and protein accumulation in neurodegenerative conditions, such as Alzheimer’s Disease (AD). However, its direct impact on the dynamics of AD-related fibril formation remains uninvestigated. We considered the effects of carnosine on the formation of fibrils/aggregates of the amyloidogenic peptide fragment Ab1-42, a major hallmark of AD injury. Atomic force microscopy and thioflavin T assays showed inhibition of Ab1-42 fibrillogenesis in vitro and differences in the aggregation state of Ab1- 42 small pre-fibrillar structures (monomers and small oligomers) in the presence of carnosine. in silico molecular docking supported the experimental data, calculating possible conformational carnosine/Ab1-42 interactions. Overall, our results suggest an effective role of carnosine against Ab1-42 aggregation.
    Full-text · Article · Jul 2013 · PLoS ONE
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    • "Within the ribosome, decreased rRNA 28S/18S ratio was observed in AD patients [51]. In addition, defective A␤ phagocytosis has also been reported [52]. All this evidence from the literature suggests that the characteristic perturbations of the five functional categories in the blood of AD patients are likely linked to the disease mechanism rather than merely sporadic obser- vations. "
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    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.
    Full-text · Article · Feb 2013 · Journal of Alzheimer's disease: JAD
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