. A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease. J Clin Invest. 2012 Apr 2;122(4):1377-92. PubMed.

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  1. In the above study, the authors developed a specific inhibitor for the receptor of advanced glycation end product (RAGE) that attenuates pathology in a mouse model of Alzheimer’s disease. They synthesized FPS-ZM1, a second-generation high-affinity RAGE-inhibitor based on our analysis of more than 5,000 small organic compounds. This new anti-RAGE tertiary amide reduces the influx of amyloid-β into the brain and suppresses the neuroinflammation in a mouse model of AD.

    FPS-ZM1 acts upon multiple cell types in vitro and in vivo to reduce the cellular stress. In addition, this compound reduces NF-κB-mediated β-secretase activity, thus reducing the amyloid production in the brain. Importantly, FPS-ZM1 is nontoxic to cells and mice.

    RAGE has been established as an important player contributing to many pathogenic mechanisms. In the above study, the authors have shown that inhibiting RAGE with this small-molecule inhibitor could be a potential therapeutic strategy for controlling disease progression in AD.

  2. This paper explores the use of two low-molecular-weight compounds that can block the interactions between Aβ peptides and RAGE. One high-affinity RAGE-specific blocker can bind to RAGE on luminal surfaces of brain vessels, but the other, called FPS-ZM1, can cross the blood-brain barrier. In doing so, FPS-ZM1 reduces significantly the amyloid load in the brains of 17-month-old APPSW mice; it also reduces the behavior defects, and microglia activation and expression of proinflammatory cytokines. FPS-ZM1 also reduces BACE1 mRNA and protein levels in the cortex and hippocampus.

    These remarkable results are produced by a 327 MW compound that has no detectable mouse toxicity. If, as the authors suggest, Aβ/RAGE interactions play a significant role in neurovascular and cognitive dysfunction, then FPS-ZM1 or compounds like it could rival the present antibody-based approach to reducing amyloid pathology in human AD brains.

  3. This most interesting paper presents a well-designed set of experiments, which provide evidence that two novel high-affinity RAGE-specific blockers inhibit Aβ40- and Aβ42-induced cellular stress in vivo and in vitro. In particular, FPS-ZM1 significantly reduced amyloid load in the brain of aged APPSW mice. In addition, it reduced various cognitive impairments as well as β-secretase activity, Aβ production, microglia activation, and neuroinflammation.

    A down side of the drug may be its main effect on amyloid, as other amyloid-centric drugs have been shown to lack clinical efficacy in AD. However, the multimodal effects of FPS-ZM1 may make it a more appropriate target for AD, a disease with multiple pathologies and behavioral impairments.

  4. A Multimodal Drug to Target Alzheimer’s Disease
    This paper describes the identification of a new RAGE (receptor for advanced glycation endproducts) blocker. Using in-vitro techniques and transgenic AD mice, the authors show that the compound FPS-ZM1: 1) crosses the blood-brain barrier, 2) inhibits Aβ40/42/RAGE binding with high affinity (3), downregulates β-secretase activity, 4) decreases Aβ oligomers and amyloid load, 5) suppresses the proinflammatory profile of microglia, and 6) improves animal behavior with no toxic effect either at cell or animal level, even at the higher dose.

    This study has investigated quite thoroughly the possible effects of FPS-ZM1 by exploring the numerous effects of RAGE in the AD brain, leading the authors to define their compound as being multimodal. Moreover, one aim of the study was to examine the effect of RAGE inhibition in advanced disease stages, conversely to the current paradigm of treating AD at the prodromal or earliest stage of the disease. Whether FPS-ZM1 also alters tau pathology remains an interesting question, particularly in light of evidence suggesting that tau phosphorylation can be induced by RAGE activation through GSK-3 (1).

    These findings are very interesting in light of the data presented on a different RAGE inhibitor, PF-04494700 developed by Pfizer (2) (CTAD, November 2011 San Diego). There, the clinical trial was halted after 12 months following worsening of the cognition in the group of patients receiving the higher dose. However, an 18-month follow-up of some of the patients showed a stabilization of the cognitive decline in the high-dose group and an improvement in the ADAS-cog score in the group with the lower dose (see ARF related news story). The causes behind the deterioration of the high-dose group are still unclear (3).

    Interestingly, the amyloid-related imaging abnormalities (ARIA) which are associated with a severe deterioration of the patients in the clinical trials of immunotherapy (4), were not observed, perhaps confirming the importance of inflammation in the development of the side effects (5).

    Nevertheless, the involvement of RAGE in both AD and diabetes, an important risk factor for AD, makes it an interesting potential target for the treatment of AD.

    References:

    . AGEs induce Alzheimer-like tau pathology and memory deficit via RAGE-mediated GSK-3 activation. Neurobiol Aging. 2011 Mar 28; PubMed.

    . PF-04494700, an oral inhibitor of receptor for advanced glycation end products (RAGE), in Alzheimer disease. Alzheimer Dis Assoc Disord. 2011 Jul-Sep;25(3):206-12. PubMed.

    . The Complexity of Sporadic Alzheimer's Disease Pathogenesis: The Role of RAGE as Therapeutic Target to Promote Neuroprotection by Inhibiting Neurovascular Dysfunction. Int J Alzheimers Dis. 2012;2012:734956. PubMed.

    . Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association Research Roundtable Workgroup. Alzheimers Dement. 2011 Jul;7(4):367-85. PubMed.

    . Neuropathology after active Abeta42 immunotherapy: implications for Alzheimer's disease pathogenesis. Acta Neuropathol. 2010 Sep;120(3):369-84. PubMed.

  5. The binding of amyloid by RAGE has been an interesting development that has long been waiting to be exploited. Unfortunately, initial efforts have not been successful in clinical trials. This multimodal drug has particularly exciting possibilities, as it may be useful against diabetic neuropathy and amyloid-induced neurodegeneration. It is also intriguing that the drug acts against multiple related targets such as BACE1, amyloid oligomers, and inflammation. The clustering of effects suggests that pleiotropic mediators of disease may be corrected by a single target. It will be very exciting to see if this drug can benefit human disease rather than only benefit the mouse model, where the deficits are direct consequences of APP overexpression and amyloid toxicity.

    Regardless of the outcome in humans, the drug can be a very useful tool to dissect out the role of the blood-brain barrier and the regulation of amyloid transport in the pathogenic cascade that leads to neurodegeneration and dementia.

  6. Alzheimer’s disease is a multifactorial and multigenetic disease. However, to procure a systems perspective on AD, it is not only important to curate a parts list of components involved in various aspects of the disease, but also to understand how they can be interlinked. This paper seems to provide part of the puzzle towards a holistic view on AD.

    Aβ accumulates as dimers, oligomers, and plaques in AD patients. While production of Aβ and its longer variant Aβ42 seems to be a causative mechanism in the early onset version of the disease, mechanisms that affect Aβ homeostasis, either through Aβ clearance or via entirely Aβ-independent mechanisms, are of principal interest in late-onset AD. Clearance of Aβ in the CNS is mediated by lipoprotein receptor-related protein (LRP), while peripheral Aβ could be pumped into the brain by receptor for advanced glycation end products (RAGE) receptors. RAGE receptors belong to the immunoglobulin superfamily and are expressed in several tissues, including the endothelium of the blood brain vessels and also in microglia. What is not known, to date, is whether RAGE-specific inhibitors can alleviate Aβ-mediated toxicity in vivo, and if such inhibitors could also affect Aβ production. The function of microglia-expressed RAGE is poorly understood. This study from the Zlokovic group now provides novel insights into the role of RAGE inhibition in AD.

    Co-first authors Rashid Deane and Itender Singh first performed a small-molecule screen to identify high-affinity Aβ/RAGE-specific inhibitors. Through next-generation modification of their primary screen hits, they designed two compounds: FPS-ZM1 and FPS2. Interestingly, because of its permeability through the blood-brain barrier (BBB), FPS-ZM1 acts both on the BBB and the CNS. FPS2, which does not cross the BBB, was used as a control for the effects of RAGE inhibition in the periphery alone. Both inhibitors, however, showed high affinity specifically to the V domain of RAGE. Importantly, these compounds did not prevent Aβ40 and Aβ42 binding to other receptors, such as LRP. Toxicity in vitro and in vivo was tested at very high concentrations, revealing the safety of both FPS-ZM1 and FPS2. An intriguing aspect of RAGE-inhibitor activity is a dual mechanism through which they act: On the one hand, as the authors show here, they dramatically reduced the influx of Aβ from the periphery to the brain in APPsw/0 mice; on the other hand, once across the BBB, they reduced BACE1 activity and Aβ production via NF-κB inhibition. The latter represents a function of RAGE in mediating the feedback signaling through which Aβ regulates its production through BACE1. Deane, Singh and colleagues further confirm the critical role of RAGE in regulating BACE1 levels in the presence of Aβ, through siRNA experiments, showing that silencing of RAGE significantly inhibited Aβ-induced BACE1 mRNA levels.

    Treating aged APPsw/0 with these new RAGE inhibitors (especially FPS-ZM1) gave surprising results, with 60-80 percent reduction of Aβ40 and Aβ42 levels in cortex and hippocampus, and with complete rescue of behavioral deficits in novel object location and novel object recognition. In fact, looking closely at the data, it seems that FPS-ZM1-treated mice performed slightly better than the non-transgenic controls. Interestingly, in the behavioral tests, FPS2, which did not cross the BBB, also seemed to rescue behavioral deficits found in non-transgenic mice. What is not clear is how FPS2 reduces Aβ40 and Aβ42 levels in the mice when it cannot get into CNS, but a definitive answer can be obtained only when we can be absolutely sure that no trace of FPS2 is found in the CNS. Furthermore, in a series of experiments, the authors show that RAGE-inhibitors modulate neuroinflammatory responses, dramatically reducing the number of activated microglia and suppressing levels of different cytokines, such as TNF-α, IL-1β, and IL-6, which play critical roles in worsening AD phenotype.

    In conclusion, this work opens a new possibility to modulate Aβ load, acting at different levels (Aβ production vs. Aβ removal) in different compartments by RAGE-specific inhibition.

  7. We are delighted that this paper generated so much interest. We believe that our findings show that our novel multimodal RAGE blocker inhibits multiple pathogenic pathways in a mouse model of Alzheimer’s disease, as well as in different cell types in vitro. It inhibits Aβ influx from the circulation across the blood-brain barrier into the brain, directly blocks microglial neuroinflammatory responses, attenuates Aβ synthesis through blockade of BACE1, and improves blood flow in response to brain activation. This compound offers new, effective ways to control progression of Aβ-mediated brain disorder in Alzheimer’s disease and other disorders associated with RAGE pathology, such as diabetes and hypertension, to name a few. We think that RAGE is still a valid target for drug therapy in AD, despite recent disappointing clinical trial results of a candidate inhibitor. Actually, in collaboration with Giuseppe Lembo's group from Rome, Italy, we have shown significant efficacy of this new RAGE blocker in a rodent model of hypertension (2012, in press).

    In response to the comment posted by Rosa Paolicelli and Lawrence Rajendran, I would like to clarify that we indeed showed, in Table 1, that the influx-selective blocker FPS2 does not cross the BBB, in contrast to FPS-ZM1. Therefore, FPS2 specifically blocks RAGE-mediated re-entry of Aβ from circulation into the brain and cannot inhibit BEC1 in the brain parenchyma, nor have direct effects on microglia in contrast to FPS-ZM1, which does all these things, thanks to its ability to penetrate the BBB.

    It is also of note, we feel, that modest effects of FPS2 on neuroinflammation and more moderate effects on blood flow regulation, behavior, and Aβ/amyloid levels are likely secondary to its ability to specifically block influx of Aβ in brain and reduce Aβ levels, which in turn may alleviate to some extent the neuroinflammation and behavior dysfunction. However, clearly the effects of FPS2 are inferior compared to FPS-ZM1, which crosses the BBB.