With the continued increase in human lifespan, the incidence of Alzheimer’s disease is rising, prompting a need for innovative therapies that can slow or stop the progression of this devastating condition. Since the discovery of the β-amyloid precursor protein site cleaving enzyme (BACE), which initiates the production of the Alzheimer’s associated peptide Aβ, it has been one of the most intensely investigated Alzheimer’s disease targets. Now, Ryan Watts and his colleagues at Genentech have used a bi-specific antibody approach to target this enzyme, which allows transport of the therapeutic antibody across the blood-brain barrier (BBB)1,2. The bi-specific antibody reduced the levels of brain Aβ more effectively than a monospecific antibody to BACE1, and this targeting approach could potentially even be applied to treat other neurological diseases. We asked three experts to comment on the implications of this study for Alzheimer’s therapy.

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Sam GandyRecently, in a tour-de-force duo of papers, Ryan Watts and colleagues have delivered advances in the two diverse areas of BACE inhibition and therapeutic delivery of biologicals across the BBB1,2. First, they described a neutralizing antibody against BACE1 with powerful Ab-lowering actions1. This is especially welcome, as pharmacological BACE inhibition, long stymied by the challenges presented by its large catalytic site, has not yet survived a phase 1 randomized human clinical trial. In addition, an antibody-based approach typically has the advantage of much greater specificity than that of small molecules. Delivery to the CNS would normally be a potential roadblock, but the authors circumvent this in their second paper by exploiting a transcytosis motif, thus enhancing delivery of BACE1-specific antibody across the BBB2.

This is all good news, but it would be more positive if the experience with Ab-lowering agents were faring better. Lilly’s g-secretase inhibitor failed in a phase 2 clinical trial last summer because it unexpectedly enhanced cognitive decline7. Bapineuzumab, the Pfizer/Johnson&Johnson monoclonal antibody against Ab, continues plugging away in phase 2, after an initial 18-month endpoint that failed to establish clinical benefit despite a mild reduction in the burden of fibrillar amyloid8. With the discovery that Ab accumulation can precede clinical symptoms by 10–20 years, the best hope for Ab-lowering interventions is probably as prophylaxis and not as therapy for symptomatic patients.

Animal data suggest that tau-lowering therapies deserve more attention, although none have advanced very far yet. Tau-targeting immunotherapy, surprisingly effective in an animal model, is probably the furthest along9,

1. Atwal, J.K. et al. A therapeutic antibody targeting BACE1 inhibits amy-loid-b production in vivo. Sci. Trans. Med. 3, 84ra43 (2011)

2. Yu, Y.J. et al. Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci. Trans. Med. 3, 84ra44 (2011)

3. Yamakawa, H. et al. b-secretase inhibitor potency is decreased by aber-rant beta-cleavage location of the “Swedish mutant” amyloid precursor protein. J. Biol. Chem. 285, 1634–1642 (2010).

4. DeMattos, R.B. et al. Peripheral anti-Ab antibody alters CNS and plasma clearance and decreases brain Ab burden in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 98, 8850–8855 (2001).

5. Vassar, R. et al. b-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735–741 (1999).

6. De Strooper, B., Vassar, R. & Golde, T. The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat. Rev. Neurol. 6, 99–107 (2010).

7. Eli Lilly. Lilly halts development of semagacestat for Alzheimer’s disease based on preliminary results of phase 3 clinical trials. <http://newsroom.lilly.com/releasedetail.cfm?releaseid=499794> (2010).

8. Rinne, J.O. et al. 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol. 9, 363–372 (2010).

9. Alzheimer Research Forum. Uppsala: Is tau immunotherapy taking off? <http://www.alzforum.org/new/detail.asp?id=2824> (2011).

10. Kim, S.H. et al. Group II metabotropic glutamate receptor stimulation triggers production and release of Alzheimer’s amyloidb42 from isolated intact nerve terminals. J. Neurosci. 30, 3870–3875 (2010).

11. Yoshimizu, T. & Chaki, S. Increased cell proliferation in the adult mouse hippocampus following chronic administration of group II metabotro-pic glutamate receptor antagonist, MGS0039. Biochem. Biophys. Res. Commun. 315, 493–496 (2004).

Alzheimer’s therapy: a BACE in the hand?

The Genentech papers describe an ingenious strategy for hijacking the normal process of transcytosis to smuggle BACE1-specific antibod-ies across the BBB1,2. BACE1 small-molecule inhibitors (SMIs) have been vigorously pursued since the discov-ery of the enzyme in 1999 (ref. 5), but ones that pen-etrate the BBB have proven chal-lenging to develop. Genentech’s bi-specific antibody overcomes this problem by incorpo-rating two different arms: one that inhibits BACE1 activity and a second that binds TfR, enabling transcytosis across the BBB. This approach has

great promise for lowering cerebral Ab amounts and may do so with greater selectivity (and hence less off-target effects) than BACE1 SMIs.

However, substantial work remains to translate the bi-specific antibody into a therapy. Chronic dosing in mice and mon-keys is necessary to show the efficacy and safety of the antibody before it’s taken into humans. TfR-related side ef fects such as

iron deficiency may not be an issue, as the antibody did not compete with transferrin binding. However, BACE1 has numerous substrates, so mechanism-based toxicity of BACE1

Robert Vassar

“Chronic dosing in mice and monkeys is necessary to show the efficacy and safety of the antibody before it’s taken into humans.”

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but it has not yet entered human trials. The most attractive feature of tau-lowering therapies is the likelihood that, if effective, they might be useful for multiple tauopathies, including frontotemporal dementia, progressive supranuclear palsy and Alzheimer’s disease.

A window of opportunity for symptomatic therapies is opening. Of these, the group 2 metabotropic glutamate inhibitors are particularly intriguing, because these drugs combine enhancement of memory, stimulation of neurogenesis and reduction of synaptic levels of Ab42 (refs. 10,11). Such a compound could conceivably offer both acute symptomatic improvement and chronic disease modification. Perhaps the combination of disillusionment with the amyloid hypothesis and the reimagining of some out-of-the-box strategies will lead to the casting of a wider net for novel, unconventional targets that bring us closer to clinical efficacy. And not a moment too soon, as the explosion of Alzheimer’s threatens citizens of Western countries whose lifespans inch toward 80 years and whose dementia costs are measured in billions of dollars.

Professor of Neurology and Psychiatry, Associate Director of the Mount Sinai Alzheimer’s Disease Research Center, Mount Sinai School of Medicine

and James J. Peters VA Medical Center, New York, New York, USA.

COMPETING FINANCIAL INTERESTSThe author declares competing financial interests: details accompany the full-text HTML version of the paper at http://www.nature.com/naturemedicine/.

Ryan Watts and his colleagues1,2 recently reported that a BACE1-specific antibody can effectively reduce brain Ab abundance in mice and in nonhuman primates. The Ab peptide Ab40, which is commonly found in Alzheimer’s disease brains, was produced in BACE1-knockout mice, suggesting that these mice have another b-secretase that can produce Ab from amyloid precursor protein (APP), possibly BACE2. The BACE1-specific antibody showed limited efficacy in the Tg2576 mouse line, which over-expresses a form of APP that carries the Swedish muta-tion found in a rare familial form of Alzheimer’s disease. However, the 5-month-old Tg2576 mice used in this exper-iment may not have accumulated high enough concentra-tions of Ab in brain, and, therefore, these mice may not be a good model for older people with Alzheimer’s. Consistent with evidence that Swedish mutant APP can be processed by BACE1 via an alternative secretory pathway3, antibody to BACE1 was less effective in blocking Ab production in this model compared to wild-type mice, in which wild-type APP is processed in an early endosome that can be targeted by the BACE1-specific antibody. Therefore, the use of the therapeutic BACE1 antibody could be limited to aged people with Alzheimer’s who do not carry the Swedish mutation.

To enhance transcytosis of the antibody across the BBB, the authors generated a bi-specific antibody combining antibody to transferrin receptor (TfR) and antibody to BACE1 (ref. 2). The affinity of TfR-specific antibody for TfR was important, as a low-affinity antibody to TfR showed optimal brain uptake owing to its ability to detach from the TfR and be released into the brain. The bi-specific anti-body accumulated in wild-type mouse brain and led to a greater reduction in brain Ab than monospecific antibody to BACE1 after a single systemic dose. However, these stud-ies should now be extended to investigate whether aged ani-mals show cognitive improvements after immunotherapy and whether this correlates with reduced concentrations of brain Ab.

It is unclear whether BACE1-specific antibody is a more effective and safe way to reduce the number and size of senile plaques than the passive Ab immunization currently in clinical trials. Importantly, Ab-specific antibodies may not need to cross the BBB, because the presence of anti-body to Ab in the periphery causes a shift in the gradient of Ab transport across the BBB, resulting in an increase in Ab efflux from the brain to blood4. Another ques-tion is whether acquired BACE1 depletion may have side effects due to insufficient processing of BACE1 substrates other than APP. It is apparent that continued comparative research will be required to assess whether antibody to BACE1 will be suitable for future clinical applications.

Professor, Department of Life Science, Graduate School of Arts & Sciences, The University of Tokyo, Tokyo, Japan.

COMPETING FINANCIAL INTERESTSThe author declares no competing financial interests.

inhibition may occur. For instance, BACE1-knockout mice are hypomy-elinated because BACE1 cleavage of neuregulin-1 is required for proper myelination6. It remains to be seen whether side effects will pose a prob-lem for therapeutic BACE1 inhibition in humans. In addition, it is unknown whether the bi-specific antibody will reduce Alzheimer’s disease pathology and improve cognition or whether it should be used before or after symp-toms occur. These are challenges fac-ing all Ab-lowering therapies.

Several other potentially effi-cacious Ab-lowering therapeutic strategies are under development6. Recent BBB-penetrant BACE1 SMIs have the advantage of oral availabil-ity and reduced cost compared with an antibody strategy, but they may be less selective than the bi-specific antibody. g-secretase SMIs decrease amounts of the toxic Alzheimer’s-associated peptide Ab42, but they also inhibit Notch, an important signaling molecule. New g-secretase

modulators that spare Notch sig-naling circumvent this problem. Antibodies to Ab effectively clear plaques, but they may cause brain inflammation in individuals with high amyloid burden. Although low-ering Ab levels may be efficacious for treating Alzheimer’s, Ab may have a normal function, so careful drug dos-ing would be required to avoid Ab deficiency.

Finally, the bi-specific antibody approach may be broadly applicable to other central nervous system diseases. The dearth of disease-modifying therapies for devastating neurode-generative disorders is tragic. The bi-specific antibody strategy now offers new hope.

Professor, Northwestern University, The Feinberg School of Medicine,

Department of Cell and Molecular Biology, Chicago, Illinois, USA.

COMPETING FINANCIAL INTERESTSThe author declares no competing financial interests.

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“The best hope for Aβ-lowering interventions is probably as prophylaxis and not as therapy.”

Shoichi Ishiura

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