Disease-modifying therapy for Alzheimer's disease: Challenges and hopes

Despite enormous efforts to develop disease-modifying drugs for Alzheimer's disease (AD), effective therapies have yet to be found. We have endured failure for a number of reasons, such as low specificity in drug candidates, inaccurate diagnosis and incorrect timing in the intervention. To help overcome these problems, modern research findings have been incorporated into new criteria and guidelines for the clinical diagnosis of AD. In addition, attempts to intervene during the earliest stages of the disease are planned, as this is probably when AD is most receptive to disease-modifying therapies. We discuss these issues and provide perspective into the future of drug development.

Disease-modifying therapy for Alzheimer's disease: Challenges and hopes

Despite enormous efforts to develop disease-modifying drugs for Alzheimer's disease (AD), effective therapies have yet to be found. We have endured failure for a number of reasons, such as low specificity in drug candidates, inaccurate diagnosis and incorrect timing in the intervention. To help overcome these problems, modern research findings have been incorporated into new criteria and guidelines for the clinical diagnosis of AD. In addition, attempts to intervene during the earliest stages of the disease are planned, as this is probably when AD is most receptive to disease-modifying therapies. We discuss these issues and provide perspective into the future of drug development.

Packed in Crystals, Bapineuzumab-Aβ Give Up Secrets

Crystals of a bapineuzumab-Aβ complex may explain how the antibody targets amyloid plaques in the brain, according to researchers in Australia. In the February 18 Scientific Reports, Michael Parker and colleagues at St. Vincent's Institute of Medical Research, Melbourne, report that bapineuzumab, a humanized mouse antibody, captures the N-terminal of Aβ in a helical conformation. This interaction may be unique. In complexes with mouse antibodies, which are used preclinically, the Aβ N-terminal exists as a random coil without secondary structure. "The thing that distinguishes bapineuzumab from the non-clinical N-terminal antibodies is that it recognizes a conformation-dependent epitope.

Bapineuzumab captures the N-terminus of the Alzheimer's disease amyloid-beta peptide in a helical conformation

Bapineuzumab is a humanized antibody developed by Pfizer and Johnson & Johnson targeting the amyloid (Aβ) plaques that underlie Alzheimer's disease neuropathology. Here we report the crystal structure of a Fab-Aβ peptide complex that reveals Bapineuzumab surprisingly captures Aβ in a monomeric helical conformation at the N-terminus. Microscale thermophoresis suggests that the Fab binds soluble Aβ(1–40) with a K_D of 89 (±9) nM. The structure explains the antibody's exquisite selectivity for particular Aβ species and why it cannot recognize N-terminally modified or truncated Aβ peptides.

Structure of the humanized 3D6 Fab-Aβ peptide complex.

Both panels show Aβ nestled in the surface of the Fab CDRs. The peptide is shown in green sticks with the light chain in light blue surface and heavy chain in a darker blue surface. (a) A 2F_o - F_c electron density map in the vicinity of the peptide contoured at 1.5σ. (b) Intra-Aβ hydrogen bonding, shown as dashed lines, stabilizes the helical conformation of the peptide.

Different conformations of the Aβ peptide.
(a) The helical conformational epitope of Aβ recognized by Bapineuzumab highlighted in green ribbon. (b) Superposition of the main-chain heavy atoms of TFE-stabilized Aβ (residues 1 to 6) NMR structures (9) (in purple) with those of Aβ as recognized by Bapineuzumab (in green). (c), (d) Superposition over light chain of Fab-Aβ complexes with murine antibody Fabs in (c) WO2-Aβ is in orange ribbon, PFA1-Aβ in yellow and (d) Bapineuzumab related Fab in grey with Aβ in green sticks.




Aβ-Fab interactions.

The Aβ residues are shown as green sticks. Amino acid sequences corresponding to the CDRs of Bapineuzumab are shown in light blue and darker blue for light and heavy chains respectively. Amino acids involved in Fab binding to Aβ are underlined and italicized in the CDR sequences common to 3D6 antibodies including Bapineuzumab. Direct polar contacts between the Fab and Aβ are shown graphically as red dashed lines. Waters involved in the hydrogen bonding network are shown as aquamarine spheres, and their putative hydrogen bonds are shown as aquamarine dashed lines. Fab residue labels and carbon atoms are colored by chain (shades of blue), whereas nitrogen, oxygen and sulfur atoms are shown in dark blue, red and yellow respectively. Surfaces represent non-polar contacts to Fab residues. Intra-chain contacts have been omitted for clarity. Figure produced using LigPlus

Current status of vaccination therapies in Alzheimer's disease

Alzheimer's disease (AD) is a major health and societal problem and is the predominant cause of dementia. Age is the major risk factor for AD, and with the predicted demographic change to an increasingly elderly population, the prevalence of the disease will reach a staggering 100 million by 2050. Acetylcholinesterase inhibitors such as donepezil, rivastigmine and galantamine offer a modest symptomatic relief for a short period of time in mild-to-moderate AD, and memantine, a low-affinity N-methyl d-aspartate receptor antagonist, is licensed for use in moderate-to-severe AD. However, none of the current therapies is able to alter the course of the disease.

Immunotherapy for Alzheimer's Disease: Rational Basis in Ongoing Clinical Trials

Amyloid-β (Aβ) immunotherapy has recently begun to gain considerable attention as a potentially promising therapeutic approach to reducing the levels of Aβ in the Central Nervous System (CNS) of patients with Alzheimer's Disease (AD). Despite extensive preclinical evidence showing that immunization with Aβ(1-42) peptide can prevent or reverse the development of the neuropathological hallmarks of AD, in 2002, the clinical trial of AN-1792, the first trial involving an AD vaccine, was discontinued at Phase II when a subset of patients immunized with Aβ(1-42) developed meningoencephalitis, thereby making it necessary to take a more refined and strategic approach towards developing novel Aβ immunotherapy strategies by first constructing a safe and effective vaccine.

The Solanezumab Benefit: small but probably real

Prospects for Alzheimer’s immunotherapy appear to have brightened. At the 137th annual meeting of the American Neurological Association in Boston, Massachusetts, researchers presented analyses from Phase 3 trials for two therapeutic antibodies, solanezumab and bapineuzumab. Most of the new data were on solanezumab, Eli Lilly and Company’s humanized monoclonal antibody against the mid-region of monomeric Aβ, and they appeared to deliver the long-awaited signal the amyloid field needed to restore its confidence after a string of clinical setbacks.