- Email: [email protected]
Alzheimer's disease and angiogenesis
CORRESPONDENCE
apolipoprotein E (APOE) genotype; the risk being highest in carriers of the ⑀4 allele.3,4 Preventive therapies for herpes simplex virus exist. If the cause of abnormal angiogenesis were established as being viral, these treatments could be used in conjunction with antiangiogenetic drugs to better fight Alzheimer’s disease. Timo E Strandberg Department of Medicine, Geriatric Clinic, University of Helsinki, PO Box 340, FIN-00029 HUS, Finland (e-mail: [email protected]) 1 2
3
4
Vagnucci AH Jr, Li WW. Alzheimer’s disease and angiogenesis. Lancet 2003; 361: 605–08. Lee S, Zheng M, Kim B, Rouse BT. Role of matrix metalloproteinase-9 in angiogenesis caused by ocular infection with herpes simplex virus. J Clin Invest 2002; 110: 1105–11. Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA. Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet 1997; 349: 241–44. Pyles RB. The association of herpes simplex virus and Alzheimer’s disease: a potential synthesis of genetic and environmental factors. Herpes 2001; 8: 64–68.
We believe that there are no grounds to abandon the “amyloid hypothesis” of Alzheimer’s disease for the “angiogenesis hypothesis”. Rather, it seems more plausible to assume that neovascularisation in the brains of individuals with Alzheimer’s disease represents a secondary event, occurring in the context of an already disturbed brain milieu attributed to A-mediated inflammation and neuronal death. Perhaps, angiogenesis is of pathological relevance to Alzheimer’s dementia, aggravating hypoxia and inflammation. However, a large body of evidence suggests that pathogenesis of the disease should be primarily considered as an imbalance between A production and clearance.2 *Eleftherios I Agorogiannis, George I Agorogiannis 12 Anthimou Gazi Street, 41222 Larissa, Greece (e-mail: [email protected]) 1 2
3
Sir—We believe Anthony Vagnucci and William Li’s assumption1 of angiogenesis as the primary event in the development of Alzheimer’s disease is improbable for various reasons. First, the recurring correlation between disease-causing gene mutations and alterations in amyloidprecursor protein metabolism emphasises a central role for A in Alzheimer’s disease,2 whatever its exact neurotoxic form (monomer, oligomer, protofibril, or fibril). Second, structural and biochemical synaptic changes in Alzheimer’s disease, obviously responsible for patients’ cognitive impairment, can arise in the absence of any other pathology, and could be attributable to the action of diffusible forms of the A peptide rather than to mature senile plaques.3 Third, other mechanisms of action rather than inhibition of angiogenesis, seem to better explain the neuroprotective and preventive effects of the drugs discussed in the hypothesis. For example, nonsteroidal anti-inflammatory drugs modulate the enzymatic activity of ␥secretase to produce more A38 and less of the more amyloidogenic and neurotoxic A42.4 Statins might lower the concentration of apolipoprotein E4, which increases A42 aggregability.2 Moreover, increases in intracellular free calcium enhance the production of amyloidogenic A,5 and this action may explain the preventive effects of channel blockers, in combination with reduction of calcium-dependent excitotoxicity.
4
5
Vagnucci AH Jr, Li WW. Alzheimer’s disease and angiogenesis. Lancet 2003; 361: 605–08. Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 2001; 81: 741–66. Selkoe DJ. Alzheimer’s disease is a synaptic failure. Science 2002; 298: 789–91. Weggen S, Eriksen JL, Das P, et al. A subset of NSAIDs lower amyloidogenic A42 independently of cyclooxygenase activity. Nature 2001; 414: 212–16. Querforth HW, Selkoe DJ. Calcium ionophore increases amyloid beta pepide production by cultured cells. Biochemistry 1994; 33: 4550–61.
Authors’ reply Sir—Hans Peter Rutz notes that hypovitaminosis D and the reduced brain expression of vitamin D hormone receptor mRNA in Alzheimer’s disease could promote the formation of harmful brain microvessels, since vitamin D is a known angiogenesis inhibitor. Vitamin D supplementation might thus be a practical antiangiogenic strategy to help protect the brain in patients with Alzheimer’s disease. We caution that pharmacological doses of vitamin D might cause hypercalcaemia. For this reason, vitamin D3 analogues, which inhibit neovascularisation but are devoid of calcaemic effects, are being developed for the antiangiogenic treatment of cancer. These could be used in an experimental study of Alzheimer’s disease. Timo Strandberg suggests connections between infection with herpes simplex virus in the Alzheimer’s brain, a homology between herpes simplex virus1 glycoprotein gB and the -amyloid protein, and the correlation between serum viral burden and cognitive impairment in elderly individuals. Viruses could trigger angiogenesis indirectly via the inflammatory response,
THE LANCET • Vol 361 • April 12, 2003 • www.thelancet.com
as observed in keratitis associated with herpes simplex virus. Another direct mechanism exists for induction of angiogenesis by herpes simplex virus. Genetic elements called CpG motifs are abundant in viral DNA. These motifs stimulate vascular endothelial growth factor (VEGF) production in vitro and angiogenesis in vivo.1 Viral infection in patients with Alzheimer’s disease could, therefore, promote brain angiogenesis via these mechanisms. Eleftherios Agorogiannis and George Agorogiannis argue persuasively that amyloid is the causative pathogenic lesion in Alzheimer’s disease. We agree with this mainstream view, which is consistent with our hypothesis. However, the “amyloid hypothesis” is not definitive. For example, the number of -amyloid brain deposits does not correlate with severity of Alzheimer’s symptoms, and some patients with deposits do not have any symptoms at all; a specific species of neurotoxic amyloid has yet to be identified; transgenic mice with -amyloid deposition do not always have neuronal damage; and -amyloid deposition does not inevitably lead to neurofibrillary tangle formation and neuronal damage.2 Other factors should, hence, be considered. We believe one such factor is abnormal brain angiogenesis, which contributes to -amyloid generation, neurodegeneration, and disease progression. The body of evidence that links angiogenesis and Alzheimer’s disease is mounting. In addition to the presence of angiogenic growth factors (VEGF, basic fibroblast growth factor [bFGF], transforming growth factor- [TGF-]) in the brain and cerebrospinal fluid of individuals with Alzheimer’s disease, the endogenous angiogenesis inhibitor endostatin was recently shown to colocalise with -amyloid in patients.3 Various proangiogenic and antiangiogenic mediators affect the milieu of the Alzheimer’s brain, with the net effect being microvascular proliferation. Interferon alfa, a clinically validated angiogenesis inhibitor, has been used to treat Alzheimer’s disease with the clinical outcome of disease stabilisation.4 Perhaps the most compelling reason to investigate angiogenesis though is found in the original report written by Alois Alzheimer himself, in which he describes the brain pathology: “besides one or several fibrils in other normal cells and numerous military foci . . . one sees endothelial proliferation and also occasionally neovascularisation.”5 We do not know if angiogenesis is the primary cause of -amyloid deposition and neurodegeneration, but emphasise the importance of understanding its role
1299
For personal use. Only reproduce with permission from The Lancet Publishing Group.
apolipoprotein E (APOE) genotype; the risk being highest in carriers of the ⑀4 allele.3,4 Preventive therapies for herpes simplex virus exist. If the cause of abnormal angiogenesis were established as being viral, these treatments could be used in conjunction with antiangiogenetic drugs to better fight Alzheimer’s disease. Timo E Strandberg Department of Medicine, Geriatric Clinic, University of Helsinki, PO Box 340, FIN-00029 HUS, Finland (e-mail: [email protected]) 1 2
3
4
Vagnucci AH Jr, Li WW. Alzheimer’s disease and angiogenesis. Lancet 2003; 361: 605–08. Lee S, Zheng M, Kim B, Rouse BT. Role of matrix metalloproteinase-9 in angiogenesis caused by ocular infection with herpes simplex virus. J Clin Invest 2002; 110: 1105–11. Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA. Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet 1997; 349: 241–44. Pyles RB. The association of herpes simplex virus and Alzheimer’s disease: a potential synthesis of genetic and environmental factors. Herpes 2001; 8: 64–68.
We believe that there are no grounds to abandon the “amyloid hypothesis” of Alzheimer’s disease for the “angiogenesis hypothesis”. Rather, it seems more plausible to assume that neovascularisation in the brains of individuals with Alzheimer’s disease represents a secondary event, occurring in the context of an already disturbed brain milieu attributed to A-mediated inflammation and neuronal death. Perhaps, angiogenesis is of pathological relevance to Alzheimer’s dementia, aggravating hypoxia and inflammation. However, a large body of evidence suggests that pathogenesis of the disease should be primarily considered as an imbalance between A production and clearance.2 *Eleftherios I Agorogiannis, George I Agorogiannis 12 Anthimou Gazi Street, 41222 Larissa, Greece (e-mail: [email protected]) 1 2
3
Sir—We believe Anthony Vagnucci and William Li’s assumption1 of angiogenesis as the primary event in the development of Alzheimer’s disease is improbable for various reasons. First, the recurring correlation between disease-causing gene mutations and alterations in amyloidprecursor protein metabolism emphasises a central role for A in Alzheimer’s disease,2 whatever its exact neurotoxic form (monomer, oligomer, protofibril, or fibril). Second, structural and biochemical synaptic changes in Alzheimer’s disease, obviously responsible for patients’ cognitive impairment, can arise in the absence of any other pathology, and could be attributable to the action of diffusible forms of the A peptide rather than to mature senile plaques.3 Third, other mechanisms of action rather than inhibition of angiogenesis, seem to better explain the neuroprotective and preventive effects of the drugs discussed in the hypothesis. For example, nonsteroidal anti-inflammatory drugs modulate the enzymatic activity of ␥secretase to produce more A38 and less of the more amyloidogenic and neurotoxic A42.4 Statins might lower the concentration of apolipoprotein E4, which increases A42 aggregability.2 Moreover, increases in intracellular free calcium enhance the production of amyloidogenic A,5 and this action may explain the preventive effects of channel blockers, in combination with reduction of calcium-dependent excitotoxicity.
4
5
Vagnucci AH Jr, Li WW. Alzheimer’s disease and angiogenesis. Lancet 2003; 361: 605–08. Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 2001; 81: 741–66. Selkoe DJ. Alzheimer’s disease is a synaptic failure. Science 2002; 298: 789–91. Weggen S, Eriksen JL, Das P, et al. A subset of NSAIDs lower amyloidogenic A42 independently of cyclooxygenase activity. Nature 2001; 414: 212–16. Querforth HW, Selkoe DJ. Calcium ionophore increases amyloid beta pepide production by cultured cells. Biochemistry 1994; 33: 4550–61.
Authors’ reply Sir—Hans Peter Rutz notes that hypovitaminosis D and the reduced brain expression of vitamin D hormone receptor mRNA in Alzheimer’s disease could promote the formation of harmful brain microvessels, since vitamin D is a known angiogenesis inhibitor. Vitamin D supplementation might thus be a practical antiangiogenic strategy to help protect the brain in patients with Alzheimer’s disease. We caution that pharmacological doses of vitamin D might cause hypercalcaemia. For this reason, vitamin D3 analogues, which inhibit neovascularisation but are devoid of calcaemic effects, are being developed for the antiangiogenic treatment of cancer. These could be used in an experimental study of Alzheimer’s disease. Timo Strandberg suggests connections between infection with herpes simplex virus in the Alzheimer’s brain, a homology between herpes simplex virus1 glycoprotein gB and the -amyloid protein, and the correlation between serum viral burden and cognitive impairment in elderly individuals. Viruses could trigger angiogenesis indirectly via the inflammatory response,
THE LANCET • Vol 361 • April 12, 2003 • www.thelancet.com
as observed in keratitis associated with herpes simplex virus. Another direct mechanism exists for induction of angiogenesis by herpes simplex virus. Genetic elements called CpG motifs are abundant in viral DNA. These motifs stimulate vascular endothelial growth factor (VEGF) production in vitro and angiogenesis in vivo.1 Viral infection in patients with Alzheimer’s disease could, therefore, promote brain angiogenesis via these mechanisms. Eleftherios Agorogiannis and George Agorogiannis argue persuasively that amyloid is the causative pathogenic lesion in Alzheimer’s disease. We agree with this mainstream view, which is consistent with our hypothesis. However, the “amyloid hypothesis” is not definitive. For example, the number of -amyloid brain deposits does not correlate with severity of Alzheimer’s symptoms, and some patients with deposits do not have any symptoms at all; a specific species of neurotoxic amyloid has yet to be identified; transgenic mice with -amyloid deposition do not always have neuronal damage; and -amyloid deposition does not inevitably lead to neurofibrillary tangle formation and neuronal damage.2 Other factors should, hence, be considered. We believe one such factor is abnormal brain angiogenesis, which contributes to -amyloid generation, neurodegeneration, and disease progression. The body of evidence that links angiogenesis and Alzheimer’s disease is mounting. In addition to the presence of angiogenic growth factors (VEGF, basic fibroblast growth factor [bFGF], transforming growth factor- [TGF-]) in the brain and cerebrospinal fluid of individuals with Alzheimer’s disease, the endogenous angiogenesis inhibitor endostatin was recently shown to colocalise with -amyloid in patients.3 Various proangiogenic and antiangiogenic mediators affect the milieu of the Alzheimer’s brain, with the net effect being microvascular proliferation. Interferon alfa, a clinically validated angiogenesis inhibitor, has been used to treat Alzheimer’s disease with the clinical outcome of disease stabilisation.4 Perhaps the most compelling reason to investigate angiogenesis though is found in the original report written by Alois Alzheimer himself, in which he describes the brain pathology: “besides one or several fibrils in other normal cells and numerous military foci . . . one sees endothelial proliferation and also occasionally neovascularisation.”5 We do not know if angiogenesis is the primary cause of -amyloid deposition and neurodegeneration, but emphasise the importance of understanding its role
1299
For personal use. Only reproduce with permission from The Lancet Publishing Group.