One bit of reassuring evidence tempered the dismay over the encephalitis cases that ended dosing in the phase 2 trial of an Aβ vaccine: At least the vaccine removed the plaques. Not so fast, write Haruhiko Akiyama of the Tokyo Institute of Psychiatry and Pat McGeer of the University of British Columbia in Vancouver in a correspondence published in the February Nature Medicine. Maybe inflammation nonspecifically instigated the plaque clearance; indeed, encephalitis resulting from any cause—not necessarily a vaccine—could lead to phagocytosis of plaques, they write.
Akiyama and McGeer present the case of a 79-year-old man with a typical case of Alzheimer's disease, who had a hemorrhagic stroke and later died of pneumonia. Upon autopsy, the area of his brain that suffered incomplete ischemia turned out to be almost devoid of amyloid plaques, while adjacent areas had abundant plaques. While the affected area had ischemic neurons, the neuropil was not necrotic. Notably, the authors describe finding many highly activated microglia in the area. Plaque clearance by phagocytosis following an infarct has been reported earlier (Wisniewski et al., 1991; Akiyama et al., 1996), and other evidence of phagocytosis of amyloid plaques exists, as well. This leads Akiyama and McGeer to conclude: "We interpret this finding as being the result of microglia and macrophage invasion of the affected area."
They go on to ask whether the plaque clearance reported by James Nicoll and colleagues in the first encephalitis autopsy case from the Elan study (see ARF related news story) may be a similar phenomenon. Akiyama and McGeer note that Nicoll and colleagues found infiltration of the brain by macrophages in this case.
With regard to the discrepancy between Aβ vaccination results in mice and humans, the authors note that the inflammatory response in mice is lower. This low-grade response might be beneficial, whereas the stronger human response becomes dangerous for cells, they suggest. "It will be important to obtain further in-vivo data from vaccinated cases through magnetic resonance imaging or, if the opportunity arises, further autopsy information. Intensive investigations into the mechanisms of vaccination-induced Aβ removal and encephalitis are needed," the authors argue.
In their reply in the same issue of Nature Medicine, Nicoll and colleagues acknowledge that their findings might have been a chance association. Even so, they point to reports of cognitive improvements of vaccinated AD patients (see ARF related news story), and to still-unpublished postmortem data of additional participants in the Elan trial which appear to confirm their initial report.
Many scientists believe that the entry of Aβ-specific antibodies into the brain triggers Aβ removal first in an early phase (within hours) that clears diffuse and soluble Aβ by an unknown mechanism, followed by a later phase (within days), during which activated microglia essentially gobble up the dense, fibrillar variety of the offending peptide. These mechanisms clearly need to be better understood, Nicoll et al. add. They write that both of the two major types of brain inflammation—microglial activation and infiltration of peripheral T cells—alone can cause acute encephalitis. Second-generation vaccines, which aim to avoid a T cell response but may still lead to microglial activation may enable scientists to distinguish between the effects of the two, Nicoll et al. add.—Hakon Heimer and Gabrielle Strobel
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- Fiala M, Liu QN, Sayre J, Pop V, Brahmandam V, Graves MC, Vinters HV. Cyclooxygenase-2-positive macrophages infiltrate the Alzheimer's disease brain and damage the blood-brain barrier. Eur J Clin Invest. 2002 May;32(5):360-71. PubMed.
- Akiyama, McGeer . .
- Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Reply to "Specificity of mechanisms for plaque removal after Abeta immunotherapy for Alzheimer disease". Nat Med. 2004 Feb;10(2):118-9. PubMed.