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Potential Therapies—Small Molecule Boosts for Immune Response, Neurogenesis
25 July 2007. Approved therapies for Alzheimer disease—acetylcholinesterase inhibitors and the NMDA antagonist, memantine—primarily tackle disease symptoms. What are badly needed are so-called disease-modifying drugs, ones that attack the underlying pathology and slow or halt disease progression. Not surprisingly, various components of the amyloid-β (Aβ) cascade have been singled out as potential disease-modifying targets, including Aβ itself and the β- and γ-secretases that are needed for its production. Two slightly different approaches to Aβ therapy are described in last week’s PNAS online. Milan Fiala, University of California School of Medicine, Los Angeles, and colleagues report that a curcuminoid boosts the immune system in AD patients and may promote clearance of Aβ, while Amelia Marutle, University of Central Florida, Orlando, and colleagues report that the multi-talented phenserine may help relieve AD-related suppression of neurogenesis.

A Plus-side to Phenserine
Phenserine, an acetylcholinesterase inhibitor, has been in the news before. Its development for AD was stopped in the fall of 2005 when phase 3 clinical trials showed that it had no effect on the primary endpoint, the ADAS-Cog test of cognition (see ARF related news story). However, in addition to blocking acetylcholinesterases, phenserine also reduces levels of Aβ and its precursor protein (APP) in neuronal cells. Though it is not clear how this reduction occurs, it seems specific to the + enantiomer, which does not inhibit esterases. Now, Marutle and colleagues show that in transgenic mouse models of AD, (+)-phenserine reduces APP levels and also stimulates differentiation of human neural stem cell progenitors into neurons. The compound may not only serve as a useful tool for studying neurogenesis in AD and other neurodegenerative disorders, but it may point the way to novel therapeutics.

To see if phenserine can lower levels of Aβ and APP in vivo, Marutle and colleagues administered the + enantiomer to APP23 mice, which produce human APP with the Swedish mutation. When given to 6- to 8-month-old mice, (+)-phenserine reduced levels of APP in the hippocampus by about 38 percent over 2 weeks. There was no effect on APP mRNA levels, suggesting that the drug acts post-transcriptionally. The authors found that levels of glial fibrillary acidic protein (GFAP) were also reduced by the compound. Because elevated GFAP in APP23 mice is due to gliogenesis, they looked to see what effect (+)-phenserine might have on neuronal stem cells. The drug reduced the number of dividing (BrdU-positive) GFAP-positive precursor cells in the hippocampi of APP23 mice that were transplanted with human neuronal stem cells (HNSCs). In contrast, the drug had no effect on the differentiation of HNSCs transplanted into wild-type mice. The results indicate that “(+)-phenserine reduces glial differentiation caused by APP overexpression,” write the authors.

If HNSCs are not differentiating into glia, then what is their fate? One possibility is that they may just be dying out, but Marutle and colleagues detected few HNSC-derived apoptotic cells in the treated animals. Another possibility is that more of the cells are going on to become fully fledged neurons. To test this, the researchers stained mouse brain tissue for human β-III tubulin, a neuronal marker. They found that in the presence of (+)-phenserine there was a significant increase (up to 112 percent) in the number of human neuronal cells in the CA1 and CA2 regions of the hippocampus and also in the motor and somatosensory cortex in APP23 mice. In wild-type mice, the phenserine treatment also induced increases in neurogenesis, but only in the CA1 region of the hippocampus.

Given the latter finding, it seems that (+)-phenserine has other effects on neurogenesis in addition to relieving suppression brought on by overproduction of human APP. “Thus, future studies will be crucial for investigating the specific molecular mechanisms underlying this phenomena [sic], as well as comparative studies for determining the efficacy of various doses of (+)-phenserine,” write the authors.

Currying Favor from the Immune System
Another approach to fighting AD progression is to promote Aβ clearance from the brain. Various active and passive immunotherapies are currently being investigated in this regard (see ARF related news story), but the paper from Fiala and colleagues suggests therapy of a slightly different flavor. They show that curcuminoids, found in turmeric and other spices, stimulate the macrophages and microglia of the innate immune system, which mop up accumulating Aβ and other undesirables.

The authors previously reported that a naturally derived curcuminoid extract spurs macrophages to take up Aβ via phagocytosis (see Zhang et al., 2006). To identify the chemical entity responsible for this stimulation, they separated and tested how individual components of the curcuminoid mixture affect Aβ uptake by human macrophages. They found that bisdesmethoxycurcumin, a minor component, was most potent at stimulating Aβ phagocytosis. The authors confirmed this when they used the chemically synthesized curcumin in the same assays.

It is not exactly clear how bisdesmethoxycurcumin stimulates Aβ phagocytosis, but the authors report that it upregulates macrophage expression of N-acetylglucosaminyltransferase III (GlcNAc-TIII) and Toll-like receptor genes. The latter play a crucial role in the innate immune system because they help cells recognize molecular patterns that are shared by many pathogens. When Fiala and colleagues added Aβ to peripheral blood mononuclear cells (PBMCs) from control volunteers, they found that these genes were upregulated in most cases. In PBMCs from AD patients, however, Aβ downregulated these genes and the curcuminoid helped to correct this. Bisdesmethoxycurcumin increased transcription of the GlcNAc-TIII gene in PBMC samples from four patients, while in the one PBMC sample tested, the curcuminoid also stimulated expression of all 10 Toll-like receptors.

Curcuminoids have been shown to be powerful antioxidants that also help break up Aβ aggregates (see ARF related news story). But this work suggests they have a third mode of action. “Thus, our results may provide an entirely different direction to therapeutic opportunities in AD through the repair of the functional and transcriptional deficits of AD macrophages by curcuminoids,” conclude the authors.—Tom Fagan.

Reference:
Marutle A, Ohmitsu M, Nilbratt M, Greig NH, Nordberg A, Sugaya K. Modulation of human neural stem cell differentiation in Alzheimer (APP23) transgenic mice by phenserine. PNAS. 2007, July 16. Abstract

Fiala M, Liu P, Espinosa-Jeffrey A, Rosenthal M, Bernard G, Ringman J, Sayre J, Zhang L, Zaghi J, Dejbakhsh S, Chiang B, Hui J, Mahanian M, Baghaee A, Hong P, Cashman J. Innate immunity and transcriptional down-regulation of MGAT-III and Toll-like receptors in Alzheimer’s disease patients are improved by bisdesmethoxycurcumin. PNAS 2007, July 16. Abstract

 
Comments on News and Primary Papers
Primary Papers: Modulation of human neural stem cell differentiation in Alzheimer (APP23) transgenic mice by phenserine.

Comment by:  Yadong Huang, ARF Advisor
Submitted 30 July 2007 Posted 30 July 2007
  I recommend this paper

Primary Papers: Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer's disease patients are improved by bisdemethoxycurcumin.

Comment by:  Sally A. Frautschy, Bruce Teter
Submitted 1 August 2007 Posted 1 August 2007

Commentary Summary
This work extends the authors’ previous studies on the role of the peripheral immune system in AD. They have reported on the infiltration of peripheral monocytes through the blood-brain barrier (BBB), a significant mechanism of clearance of amyloid from the brain, and that peripheral macrophages from AD patients are defective in Aβ phagocytosis. These are important findings, and if other groups can confirm defects of Aβ uptake in Alzheimer patients’ macrophages, it may become a useful diagnostic assay. The present work further characterizes this defective phagocytosis to include defective intracellular trafficking of Aβ and phenotypic response to amyloid in AD brain tissue, as well as identifying a novel gene (MGAT) suggested to play a role in the defective phenotype.

The title and press releases surrounding this work emphasize the ability of a curcumin family compound (bisdesmethoxycurcumin, BDM-Curc) to correct the putative phagocytosis defect in AD. The structural characteristics of curcumin (Curc), enabling it to inhibit...  Read more

View all comments by Sally A. Frautschy
View all comments by Bruce Teter


Comment by:  Milan Fiala (Disclosure)
Submitted 6 August 2007 Posted 6 August 2007

Reply to Frautschy, Teter Comment

In response to the comments by Frautschy and others, the objectives of our paper are first to explain the immune mechanisms of amyloidosis in Alzheimer disease patients and second to find out what can be done about clearance of amyloidosis from the patient’s brain. The emerging answers are that amyloidosis is contributed by insufficient clearance by the Alzheimer patients’ innate immune system and that modulation of the innate immune system has positive effects on amyloid-β clearance.

There is no problem in distinguishing FITC-amyloid-β by fluorescence microscopy from curcuminoids, which (at 0.1 microM) are not visible by fluorescence microscopy. Amyloid-β is also revealed by immunostaining with amyloid-β antibody or by electron microscopy. This can be seen in the pictures of FITC-Aβ in Figs. 2, 3, 5 in the current PNAS publication (1) or the Figs. 2 and 3 (using anti-Aβ immunofluorescence or electron microscopy) in our previous publication (2). The responses of individual patients and...  Read more

View all comments by Milan Fiala

Comments on Related News
Related News: Curry Ingredient Spices Things Up by Blocking Aβ Aggregation

Comment by:  Erik Jansson
Submitted 26 December 2004 Posted 28 December 2004
  I recommend the Primary Papers

Curcumin also impacts aluminum binding to chromatin DNA, which is of relevance. After aluminum mordanting of chicken blood smears, several chelating dyes and reagents were found to detect metal binding to chromatin DNA by fluorescence microscopy. One of them [the reagents] was curcumin. Aluminum is a risk factor for AD.

References:
A.R. Llorente, P. Del Castillo, J.C. Stockert, Aluminum binding to chromatin DNA as revealed by formation of fluorescent complexes with 8-hydroxyquinoline and other ligands. J. Microsc 155 (Pt. 2) (1989) 227-30

View all comments by Erik Jansson

Related News: Curry Ingredient Spices Things Up by Blocking Aβ Aggregation

Comment by:  J. Lucy Boyd
Submitted 1 February 2005 Posted 1 February 2005
  I recommend the Primary Papers

Related News: Neurogenesis Gets a Jolt From Enhanced APP Processing, Curcumin

Comment by:  Gregory Cole, ARF Advisor
Submitted 4 April 2008 Posted 4 April 2008

This new data on curcumin stimulated neurogenesis look pretty good and the dosing at 500nM to get the effect in vitro and via stimulation of MAPK is credible and consistent with other literature. Their in vivo results are the most important demonstration of possible utility. The dosing is higher than what people achieve with current supplements and the blood and brain levels represent estimates. They are at the high end, but the authors get the neurogenesis effect without toxicity, suggesting that it may be realizable within a therapeutic window.

One caveat for the relevance to AD for this and for most of the other studies showing stimulation of hippocampal neurogenesis is that the effects shown are usually in the dentate gyrus rather than in more AD vulnerable regions like CA1, entorhinal cortex and other areas showing neuron loss. That said, the increases in areas with normal neurogenesis, in the DG and in the cortical subventricular zone, suggests an effect might extend to other areas and might redistribute to areas of neuron loss in the presence of regional pathology.

View all comments by Gregory Cole


Related News: Neurogenesis Gets a Jolt From Enhanced APP Processing, Curcumin

Comment by:  Tommaso Russo, ARF Advisor
Submitted 9 April 2008 Posted 9 April 2008

This interesting paper of Thomas Willnow and colleagues confirms that SORLA/LR11 has a significant role in the regulation of APP processing, thus giving further support to the hypothesis that reduced SORLA expression could be a risk factor for sporadic AD (Rogaeva et al., 2007).

In addition, the results suggest some other reflections. First, they confirm that, at least in mice, altered neuronal function and survival are not directly correlated with the amount of Aβ produced and with plaque burden. This is the umpteenth observation that draws our attention to this point, but we still don’t have a clear explanation for that. Second, the results contribute to the unsolved issue of APP functions. The observed molecular phenotypes are actually due to an increased processing of APP that leads to accumulation of secreted soluble APP. However, we should also take into account that increased processing of APP is also expected to affect AICD intracellular concentration. Thus, we cannot exclude that the observed phenotype could be due to altered AICD-dependent signaling. This...  Read more

View all comments by Tommaso Russo

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