The creative approach reported by Arbel and colleagues to reduce Aβ burden using site-directed APP antibodies that inhibit β-cleavage offers a possible alternative to specific BACE inhibitors, which have been challenging to design and could interfere with the processing of BACE substrates likely to be uncovered in the future. Another attractive feature of the approach is that it strategically targets APP processing within the endocytic pathway, the site of the earliest appearing cellular disturbances related to AD and a likely source for Aβ overproduction in sporadic AD. The approach has a possible advantage over immunization strategies directed squarely at β-amyloid removal: Blocking Aβ production may allow for a more gradual process of amyloid/Aβ clearance better tolerated by the cerebral vasculature. One possible disadvantage, however, is that the β-site-directed antibodies also cross-react with APP holoprotein and may, therefore, affect its function adversely.

Judgments about the promise of this approach as a possible therapy rest on confirming the provocative, though...  Read more

The creative approach reported by Arbel and colleagues to reduce Aβ burden using site-directed APP antibodies that inhibit β-cleavage offers a possible alternative to specific BACE inhibitors, which have been challenging to design and could interfere with the processing of BACE substrates likely to be uncovered in the future. Another attractive feature of the approach is that it strategically targets APP processing within the endocytic pathway, the site of the earliest appearing cellular disturbances related to AD and a likely source for Aβ overproduction in sporadic AD. The approach has a possible advantage over immunization strategies directed squarely at β-amyloid removal: Blocking Aβ production may allow for a more gradual process of amyloid/Aβ clearance better tolerated by the cerebral vasculature. One possible disadvantage, however, is that the β-site-directed antibodies also cross-react with APP holoprotein and may, therefore, affect its function adversely.

Judgments about the promise of this approach as a possible therapy rest on confirming the provocative, though very preliminary, findings in the mouse amyloidopathy model and establishing that the mechanism of action demonstrated in the cell culture experiments applies in all respects to the Aβ lowering seen in brain. The much greater effect seen in vivo than in vitro needs to be understood. The 8-month age of the Tg2576 mice analyzed in the study is a possible factor to consider in this regard because the amyloid phenotype is quite variable at this young age.

View all comments by Ralph Nixon

Recent exciting work from Beka Solomon’s group demonstrates proof-of-concept for a novel way to block β-secretase activity using active immunization in mice to generate antibodies directed against the β-secretase cleavage site of APP. In a paper by Arbel et al., WT mice were immunized with a multiple antigen peptide containing eight copies of an eight-residue peptide representing the site at which β-secretase cleaves APP. To enhance immunogenicity, one of the two mutant residues found in the APP Swedish mutation was used in the immunogen. Antibodies were generated, purified, and used for in vitro studies of APP processing and Aβ generation in hAPPWT-transfected CHO cells. The antibodies recognized full-length APP but not Aβ. When co-incubated with APP-CHO cells, the antibodies were internalized, colocalized with APP in early endosomes, and resulted in reduced intracellular Aβ (50 percent by 5 days) and extracellular Aβ (22 percent at 9 hours, but effect wore off later). APP CTF C99 was also diminished. Preliminary data from a pilot study in 8-month-old APP Tg2576 mice showed...  Read more

Recent exciting work from Beka Solomon’s group demonstrates proof-of-concept for a novel way to block β-secretase activity using active immunization in mice to generate antibodies directed against the β-secretase cleavage site of APP. In a paper by Arbel et al., WT mice were immunized with a multiple antigen peptide containing eight copies of an eight-residue peptide representing the site at which β-secretase cleaves APP. To enhance immunogenicity, one of the two mutant residues found in the APP Swedish mutation was used in the immunogen. Antibodies were generated, purified, and used for in vitro studies of APP processing and Aβ generation in hAPPWT-transfected CHO cells. The antibodies recognized full-length APP but not Aβ. When co-incubated with APP-CHO cells, the antibodies were internalized, colocalized with APP in early endosomes, and resulted in reduced intracellular Aβ (50 percent by 5 days) and extracellular Aβ (22 percent at 9 hours, but effect wore off later). APP CTF C99 was also diminished. Preliminary data from a pilot study in 8-month-old APP Tg2576 mice showed improved cognition and reduced cerebral Aβ burden in immunized mice compared to nonimmunized controls. The authors suggest that the antibodies cross the blood-brain barrier (BBB) and inhibit β-secretase activity in the brain, although evidence for this is not yet provided. Unfortunately, the authors confused our previously published work as evidence that Aβ antibodies cross the BBB and bind plaques following passive immunization in APP Tg mice. In our paper by Seabrook et al., we used active immunization with human or rodent Aβ peptides and showed that mouse Ig could be immunohistochemically detected in plaques in both immunized and nonimmunized mouse brain cryosections, similar to findings of human IgG in cerebral plaques of brain tissue from Aβ-immunized and nonimmunized AD patients as reported by Nicoll et al. Aβ-specific immunoglobulins were undetectable in brain by ELISA or Western blot. Thus, our results do not provide evidence that Aβ antibodies cross the BBB and bind plaques.

The novel method of blocking β-secretase activity described by Arbel et al. using immunotherapy is creative and exciting. It will be interesting to learn more about the effects of such an immunogen in vivo, including a full analysis of both the humoral and cellular immune responses. A robust T cell response to APP via active immunization may wreak havoc on the body, indicating that passive transfer of antibodies against the β-secretase cleavage site of APP may be a safer alternative.

References:
Arbel M, Yacoby I, Solomon B. Inhibition of amyloid precursor protein processing by {beta}-secretase through site-directed antibodies. Proc Natl Acad Sci U S A. 2005 May 13; [Epub ahead of print] Abstract

Seabrook TJ, Bloom JK, Iglesias M, Spooner ET, Walsh DM, Lemere CA. Species-specific immune response to immunization with human versus rodent A beta peptide. Neurobiol Aging. 2004 Oct;25(9):1141-51. Abstract

Nicoll J, Wilkinson D, Holmes C, Steart P, Markham H, Weller R. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003 Apr;9(4):448-52. Epub 2003 Mar 17. Abstract

View all comments by Cynthia Lemere

Our article is related to the very important accelerated endocytosis process as presented firstly by the Nixon group. The question of what leads to this process is key for understanding the early process of AD. I believe that a clue can be attained from Down syndrome (DS) cases. As the Nixon group has previously shown, the accelerated endocytosis is clearly present in DS as well as sporadic forms of AD at the very early stages.

DS is caused by triplication of chromosome 21. By brief examination of this chromosome, I have seen some interesting genes that are related to the endocytosis process. Two of them, coding for the proteins synaptojanin and synaptogamin, might be related to the accelerated endocytosis. In Down syndrome and in the sporadic form of AD, overexpression of these genes may be a result of a defect in cholesterol homeostasis, for example, malfunctions of cholesterol uptake from the bloodstream (related to ApoE activity?). The cells may accelerate endocytosis as a mechanism to increase cholesterol uptake to compensate for the faulty cholesterol endocytosis....  Read more

Our article is related to the very important accelerated endocytosis process as presented firstly by the Nixon group. The question of what leads to this process is key for understanding the early process of AD. I believe that a clue can be attained from Down syndrome (DS) cases. As the Nixon group has previously shown, the accelerated endocytosis is clearly present in DS as well as sporadic forms of AD at the very early stages.

DS is caused by triplication of chromosome 21. By brief examination of this chromosome, I have seen some interesting genes that are related to the endocytosis process. Two of them, coding for the proteins synaptojanin and synaptogamin, might be related to the accelerated endocytosis. In Down syndrome and in the sporadic form of AD, overexpression of these genes may be a result of a defect in cholesterol homeostasis, for example, malfunctions of cholesterol uptake from the bloodstream (related to ApoE activity?). The cells may accelerate endocytosis as a mechanism to increase cholesterol uptake to compensate for the faulty cholesterol endocytosis.

Overexpression of these two proteins in combination with APP may shed more light on this very early stage of the disease. It is interesting to note that these proteins are missing from the mouse chromosome 17, which is the mouse homolog to chromosome 21. Addition of APP and synaptojanin and synaptogamin to a mouse model of DS or vice versa, addition of synaptojanin and synaptogamin to hAPP mouse models, would create a much more realistic model of sporadic cases.

View all comments by Iftach Yacoby