Donner L, Fälker K, Gremer L, Klinker S, Pagani G, Ljungberg LU, Lothmann K, Rizzi F, Schaller M, Gohlke H, Willbold D, Grenegard M, Elvers M. Platelets contribute to amyloid-β aggregation in cerebral vessels through integrin αIIbβ3-induced outside-in signaling and clusterin release. Sci Signal. 2016 May 24;9(429):ra52. PubMed.

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  1. This research by Donner and colleagues makes important contributions in understanding mechanistically how amyloid is deposited in cerebral amyloid angiopathy. It appears that platelets play an important role in Aβ fibrillization. Specifically, amyloid appears to bind to integrin, which stimulates ADP and clusterin secretion from platelets. The clusterin then promotes amyloid aggregation, which leads to accumulation. This explains, in essence, how amyloid is bound to vessel walls.

    Also important to this observation is the evidence that clopidogrel could reduce this process by inhibiting clusterin release. Clopidogrel is typically not considered for CAA or AD. Thus, from a therapeutic standpoint, it could prove important to prevent amyloid deposition in blood vessel walls, which could in turn reduce the complications of the angiopathy. Ironically, this is counterintuitive because we typically avoid anti-platelet treatments in hemorrhagic events such as CAA.

    View all comments by Marwan Sabbagh

  2. This recent article of Donner et al. provides an elegant series of largely ex vivo experiments to demonstrate how soluble Aβ peptide can activate cultured platelets, cause release of the Aβ chaperone clusterin, and promote Aβ aggregation. These processes were shown to be mediated by the RHDS motif of Aβ interacting with the platelet surface integrin α11bβ3, stimulating an outside-in signaling cascade that facilitates clusterin release and Aβ aggregation. Interestingly, platelets from patients with Glanzman thrombasthenia (GT), which have markedly reduced levels of dysfunctional α11bβ3, were deficient in clusterin release and in promotion of Aβ aggregation, further connecting these two events in these experiments. The most intriguing aspect of the work involved studies with APP23 transgenic mice that overexpress human AβPP and develop both brain parenchymal and vascular amyloid deposition. The authors show that treatment of APP23 mice with the anti-platelet drug clopidogrel appears to reduce the number of vessels with amyloid deposits and the adherence of platelets to these vessels. These findings provide evidence that platelets may contribute to the development of cerebral vascular amyloid formation and could provide a target to treat the condition of cerebral amyloid angiopathy.

    The notion that platelets could play a role in Alzheimer’s disease pathology has been considered for more than 25 years now, following the initial discovery that platelets contain very high levels of AβPP (Van Nostrand et al., 1990; Bush et al., 1990) and can release primarily Aβ40 peptide upon activation, although these levels are quite low at the pg/ml level (Li et al., 1998; Casoli et al., 2007). Clusterin has been recognized as an important chaperone for Aβ that can promote its fibrillar assembly, and clusterin absence dramatically reduces amyloid plaque formation in human AβPP transgenic mice (Demattos et al., 2002). The present study ties these previous findings together, providing a potential mechanism as to how platelets can facilitate cerebral vascular amyloid formation.

    As intriguing as these findings are, they raise a number of key follow-up questions to ascertain the importance of this mechanism to cerebral vascular amyloid formation. First, what is the source of Aβ that can promote such interactions with platelets and lead to vascular amyloid formation? As mentioned above, although platelets contain very high levels of AβPP, the vast majority of this appears to be processed by the non-amyloidogenic α-secretase pathway. Therefore, platelets seem to contain very low (pg) amounts of Aβ. The studies presented in this article required micromolar concentrations of Aβ40 to promote stimulation of platelets and aggregation of Aβ. On the other hand, there is strong evidence, particularly with transgenic mouse models, that in the brain neuronal production of Aβ causes cerebral vascular amyloid formation (Calhoun et al., 1998; Davis et al., 2004). Further, vascular amyloid formation occurs on the abluminal side of cerebral capillaries and in the tunica media of small arterioles. Thus, the question as to how the initial seeding and expansion of abluminal vascular amyloid could be initiated by circulating platelets needs to be addressed. Perhaps platelets play a role later in the disease when there is compromise of vascular integrity and exposure to platelet components. 

    Second, although the most common form of cerebral amyloid angiopathy (CAA) involves Aβ, numerous other amyloidogenic proteins can cause this condition, including prion proteins, cystation C, amyloid British protein, amyloid Danish protein, gelsolin, and others. Since these amyloid proteins do not harbor the RHDS motif of Aβ, which appears to be important for promoting the platelet responses, are markedly different mechanisms involved in these CAA disorders? Also, secreted sAβPPα, which harbors the “RHDS” motif at its C-terminal end, is released at very high levels from activated platelets. Can this species of sAβPPα also interact with the platelet surface integrin α11bβ3 to promote platelet outside-in signaling and clusterin release? Can it block Aβ interactions with platelets and Aβ aggregation?

    Finally, the authors suggest that anti-platelet therapy may be useful for treating CAA. As in most cases, this type of approach is a double-edged sword. Indeed, CAA can promote small vessel occlusions, which clog up with platelets as the authors previously showed. In this case, preventing the adherence and clumping of platelets could be helpful. However, CAA can also cause loss of vessel integrity and hemorrhage. In this case, preventing platelets from serving their normal function in forming a thrombotic plug would be counterproductive and prolong detrimental bleeding into the brain. Although these are significant questions that need to be addressed in future studies, the present article continues to support the important concept of vascular contributions to Alzheimer’s disease.

    References:

    Bush AI, Martins RN, Rumble B, Moir R, Fuller S, Milward E, Currie J, Ames D, Weidemann A, Fischer P. The amyloid precursor protein of Alzheimer's disease is released by human platelets. J Biol Chem. 1990 Sep 15;265(26):15977-83. PubMed.

    Calhoun ME, Burgermeister P, Phinney AL, Stalder M, Tolnay M, Wiederhold KH, Abramowski D, Sturchler-Pierrat C, Sommer B, Staufenbiel M, Jucker M. Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):14088-93. PubMed.

    Casoli T, Di Stefano G, Giorgetti B, Grossi Y, Balietti M, Fattoretti P, Bertoni-Freddari C. Release of beta-amyloid from high-density platelets: implications for Alzheimer's disease pathology. Ann N Y Acad Sci. 2007 Jan;1096:170-8. PubMed.

    Davis J, Xu F, Deane R, Romanov G, Previti ML, Zeigler K, Zlokovic BV, Van Nostrand WE. Early-onset and robust cerebral microvascular accumulation of amyloid beta-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid beta-protein precursor. J Biol Chem. 2004 May 7;279(19):20296-306. Epub 2004 Feb 25 PubMed.

    Demattos RB, O'Dell MA, Parsadanian M, Taylor JW, Harmony JA, Bales KR, Paul SM, Aronow BJ, Holtzman DM. Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10843-8. PubMed.

    Li QX, Whyte S, Tanner JE, Evin G, Beyreuther K, Masters CL. Secretion of Alzheimer's disease Abeta amyloid peptide by activated human platelets. Lab Invest. 1998 Apr;78(4):461-9. PubMed.

    Van Nostrand WE, Schmaier AH, Farrow JS, Cunningham DD. Protease nexin-II (amyloid beta-protein precursor): a platelet alpha-granule protein. Science. 1990 May 11;248(4956):745-8. PubMed.

    View all comments by William Van Nostrand

  3. Aβ peptides accumulate in cerebral vessels, causing cerebral amyloid angiopathy (CAA), and in brain parenchyma correlating with Alzheimer’s disease (AD). It is known that besides neurons, circulating platelets contain high amount of Aβ peptides. Upon activation, platelets release Aβ in the circulation, which in turn reinforce platelet adhesion, activation, and aggregation. Platelets are also able to mobilize soluble Aβ peptides into fibrillary Aβ and induce fibrillar Aβ aggregate formation in culture.

    In this recent paper in Science Signaling, the group of Margitta Elvers demonstrates that soluble Aβ40, via its RHDS sequence, is able to bind integrin αIIbβ3. This binding induces platelet adhesion and integrin αIIbβ3 outside-in activation and promotes release of clusterin and ADP. Clusterin is a chaperone that is associated with the severity of AD and influences the structure and toxicity of Aβ peptides, contributing to the formation Aβ fibrils. ADP is a platelet agonist. We have previously demonstrated that it plays a crucial role in Aβ peptide-induced platelet activation (Canobbio et al., 2014). Here the authors confirm our observation and demonstrated that ADP is also important in platelet-mediated fibril formation. All these data point to a pivotal role of platelets and ADP in Aβ deposition and oligomerization in cerebral vessels. More interestingly, the authors demonstrate that treating AD mice (APP23) with the ADP receptor P2Y12 antagonist clopidogrel (commonly used in anti-platelet therapies), inhibits platelet activation and clusterin release and decreases CAA. These results open new perspectives on novel therapeutic approaches to prevent Aβ fibril formation and CAA development. 

    References:

    Canobbio I, Guidetti GF, Oliviero B, Manganaro D, Vara D, Torti M, Pula G. Amyloid β-peptide-dependent activation of human platelets: essential role for Ca2+ and ADP in aggregation and thrombus formation. Biochem J. 2014 Sep 15;462(3):513-23. PubMed.

    View all comments by Ilaria Canobbio

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