This paper describes a mechanism by which macrophages may participate in the development of congophilic amyloid angiopathy. The results are consistent with Aβ-engorged macrophages being unable to transit across the endothelial cell barrier, ultimately succumbing to toxic actions of extracellular Aβ, and disgorging their contents near the vessels. Such a mechanism may explain why anti-Aβ antibodies promote congophilic angiopathy, which by itself may increase the risk of microhemorrhage, as observed with immunotherapy (Pfeifer et al., 2003; Wilcock et al., 2004; Racke et al., 2005; Schroeder et al., 2008; Boche et al., 2008). The mechanisms may also explain why antibodies which do not facilitate macrophage phagocytosis, via Fc receptor interactions, may minimize these potentially adverse consequences (Wilcock et al., 2006).

References:
Wilcock DM, Alamed J, Gottschall PE, Grimm J, Rosenthal A, Pons J, Ronan V, Symmonds K, Gordon MN, Morgan D. Deglycosylated anti-amyloid-beta antibodies eliminate cognitive deficits and reduce parenchymal amyloid with minimal vascular consequences in aged amyloid precursor protein transgenic mice. J Neurosci. 2006 May 17;26(20):5340-6. Abstract

Wilcock DM, Rojiani A, Rosenthal A, Subbarao S, Freeman MJ, Gordon MN, Morgan D. Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. J Neuroinflammation. 2004 Dec 8;1(1):24. Abstract

Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, Mathews PM, Jucker M. Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science. 2002 Nov 15;298(5597):1379. Abstract

Racke MM, Boone LI, Hepburn DL, Parsadainian M, Bryan MT, Ness DK, Piroozi KS, Jordan WH, Brown DD, Hoffman WP, Holtzman DM, Bales KR, Gitter BD, May PC, Paul SM, Demattos RB. Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta. J Neurosci. 2005 Jan 19;25(3):629-36. Abstract

Schroeter S, Khan K, Barbour R, Doan M, Chen M, Guido T, Gill D, Basi G, Schenk D, Seubert P, Games D. Immunotherapy reduces vascular amyloid-beta in PDAPP mice. J Neurosci. 2008 Jul 2;28(27):6787-93. Abstract

Boche D, Zotova E, Weller RO, Love S, Neal JW, Pickering RM, Wilkinson D, Holmes C, Nicoll JA. Consequence of Abeta immunization on the vasculature of human Alzheimer's disease brain. Brain. 2008 Dec;131(Pt 12):3299-310. Abstract

View all comments by Dave Morgan

We thank Dr. Morgan for his comment. We do believe that deficient innate immune clearance of amyloid-β plays an important role in Alzheimer disease that is often overlooked in this field. Our laboratory is investigating potential targeted therapeutics that may alleviate some of the immunological deficiencies of AD patients. For example, we chose to study curcuminoids (from Indian curry root) because of the lower occurrence of AD in India, where curry is a staple of the country’s cuisine (4). Our in-vitro studies provide evidence that curcuminoids could play an important role in treating innate immune deficiencies, including amyloid-β phagocytosis as well as TLR and MGAT-3 expression (1,6).

We most recently directed our attention to vitamin D, and found that in vitro it significantly enhances amyloid-β phagocytosis in AD macrophages and also plays an anti-apoptotic role (2). These results are encouraging, especially in light of clinical data suggesting that vitamin D levels in blood serum of Alzheimer patients are significantly lower than control subjects (3,5). It can be...  Read more

We thank Dr. Morgan for his comment. We do believe that deficient innate immune clearance of amyloid-β plays an important role in Alzheimer disease that is often overlooked in this field. Our laboratory is investigating potential targeted therapeutics that may alleviate some of the immunological deficiencies of AD patients. For example, we chose to study curcuminoids (from Indian curry root) because of the lower occurrence of AD in India, where curry is a staple of the country’s cuisine (4). Our in-vitro studies provide evidence that curcuminoids could play an important role in treating innate immune deficiencies, including amyloid-β phagocytosis as well as TLR and MGAT-3 expression (1,6).

We most recently directed our attention to vitamin D, and found that in vitro it significantly enhances amyloid-β phagocytosis in AD macrophages and also plays an anti-apoptotic role (2). These results are encouraging, especially in light of clinical data suggesting that vitamin D levels in blood serum of Alzheimer patients are significantly lower than control subjects (3,5). It can be argued that Alzheimer disease patients have lower blood serum vitamin D levels because they are less active than the general population and consequently have less exposure to sunlight. Nevertheless, we have data to suggest that increased vitamin D levels can enhance the innate immune function of AD patients. These results have been prepared in a manuscript which was accepted for publication by the Journal of Alzheimer’s Disease.

Finally, Dr. Morgan's explanation concerning anti-Aβ antibodies promoting congophilic angiopathy is insightful. We commend Dr. Morgan on his group's discovery that deglycosylating IgGs is one way to decrease Aβ in the brains of APP-transgenic mice without the adverse vascular effects of unmodified anti-Aβ antibodies.

References:
1. Fiala M, Liu PT, Espinosa-Jeffrey A, Rosenthal MJ, Bernard G, Ringman JM, Sayre J, Zhang L, Zaghi J, Dejbakhsh S, Chiang B, Hui J, Mahanian M, Baghaee A, Hong P, Cashman J (2007) Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer's disease patients are improved by bisdemethoxycurcumin. Proc Natl Acad Sci U S A 104:12849-12854. Abstract

2. Masoumi A, Goldenson B, Ghirmai S, Avagyan H, Zaghi J, Abel K, Zheng X, Espinosa-Jeffrey A, Mahanian M, Liu PT, Hewison M, Mizwicki M, Cashman J, Fiala M (2009) 1alpha,25-dihydroxyvitamin D3 interacts with curcuminoids to stimulate amyloid-beta clearance by macrophages of Alzheimer disease patients. J Alzheimers Dis.

3. Przybelski RJ, Binkley NC (2007) Is vitamin D important for preserving cognition? A positive correlation of serum 25-hydroxyvitamin D concentration with cognitive function. Arch Biochem Biophys 460:202-205. Abstract

4. Ringman JM, Frautschy SA, Cole GM, Masterman DL, Cummings JL (2005) A potential role of the curry spice curcumin in Alzheimer's disease. Curr Alzheimer Res 2:131-136. Abstract

5. Wilkins CH, Sheline YI, Roe CM, Birge SJ, Morris JC (2006) Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults. Am J Geriatr Psychiatry 14:1032-1040. Abstract

6. Zhang L, Fiala M, Cashman J, Sayre J, Espinosa A, Mahanian M, Zaghi J, Badmaev V, Graves MC, Bernard G, Rosenthal M (2006) Curcuminoids enhance amyloid-beta uptake by macrophages of Alzheimer's disease patients. J Alzheimers Dis 10:1-7. Abstract

View all comments by Justin Zaghi

This interesting paper by Hawkes and McLaurin provides additional evidence that blood-borne macrophages are competent Aβ phagocytes. Their work further cements concepts from previous reports, which showed that blood-derived monocytes exist near cerebral vessels and β amyloid plaques (Stalder et al., 2005), and that genetic ablation of these cells increases parenchymal β amyloid load in mouse models of AD (Simard et al., 2006; El Khoury et al., 2007). Further, we have recently shown that genetic interruption of transforming growth factor-β signaling in innate immune cells results in accumulation of macrophages in cerebral vessels, brain penetration of these cells, and their clearance of both cerebral vascular and parenchymal β amyloid deposits in AD model mice (Town et al., 2008).

Hawkes and McLaurin specifically draw attention to the perivascular macrophage subset. They have performed two definitive in-vivo experiments to discern the functional role of these cells in the context of AD-like pathology in TgCRND8 mice: 1) they reduced numbers of perivascular macrophages using...  Read more

This interesting paper by Hawkes and McLaurin provides additional evidence that blood-borne macrophages are competent Aβ phagocytes. Their work further cements concepts from previous reports, which showed that blood-derived monocytes exist near cerebral vessels and β amyloid plaques (Stalder et al., 2005), and that genetic ablation of these cells increases parenchymal β amyloid load in mouse models of AD (Simard et al., 2006; El Khoury et al., 2007). Further, we have recently shown that genetic interruption of transforming growth factor-β signaling in innate immune cells results in accumulation of macrophages in cerebral vessels, brain penetration of these cells, and their clearance of both cerebral vascular and parenchymal β amyloid deposits in AD model mice (Town et al., 2008).

Hawkes and McLaurin specifically draw attention to the perivascular macrophage subset. They have performed two definitive in-vivo experiments to discern the functional role of these cells in the context of AD-like pathology in TgCRND8 mice: 1) they reduced numbers of perivascular macrophages using clodronate, and 2) increased turnover of these cells using chitin. Results from both experiments suggest that perivascular macrophages are an important class of Aβ phagocytes that serve to limit cerebral amyloid angiopathy. Interestingly, these cells were unable to migrate into the brain parenchyma, and instead were restricted to cerebral vessels. It will be important to further discern the signals necessary to promote both brain penetration of these cells and Aβ engulfment/clearance in the AD brain. Elucidation of these signals will likely lead to novel therapeutic targets for the human syndrome.

References:
El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, Luster AD. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med. 2007 Apr;13(4):432-8. Abstract

Simard AR, Soulet D, Gowing G, Julien JP, Rivest S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron. 2006 Feb 16;49(4):489-502. Abstract

Stalder AK, Ermini F, Bondolfi L, Krenger W, Burbach GJ, Deller T, Coomaraswamy J, Staufenbiel M, Landmann R, Jucker M. Invasion of hematopoietic cells into the brain of amyloid precursor protein transgenic mice. J Neurosci. 2005 Nov 30;25(48):11125-32. Abstract

Town T, Laouar Y, Pittenger C, Mori T, Szekely CA, Tan J, Duman RS, Flavell RA. Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat Med. 2008 Jun;14(6):681-7. Abstract

View all comments by Terrence Town