Commentary on "Alzheimer's disease drug development and the problem of the blood-brain barrier." Alzheimer's disease drugs: more than one barrier to breach.

An intact blood-brain barrier (BBB) hinders access by therapeutic agents with large molecular masses or high hydrophilic indices. This obstacle has become an acute issue in the field of Alzheimer’s disease (AD) therapeutic interventions where clinical trial failures have been frequent. To overcome these problems, Dr. Pardridge and colleagues [1] suggest the use of antibody fusion constructs promoting bi-directional transport across the BBB of disaggregated Ab peptides and delivery of brain neurotrophic factors. This Trojan horse concept is based on the creation of chimeras in which the human insulin receptor monoclonal antibody (HIRMab) is fused to the Fc neonatal receptor antibody and anti-Ab peptide antibody to promote mobilization of amyloid out of the brain. A similar approach would enable the specific delivery of neurotrophic factors such as BDNF and GDNF linked to the HIRMab into the central nervous system. In principle, chimeric molecule therapies offer a creative and elegant approach toward circumventing the BBB to deliver critical growth factors and facilitate the removal of noxious substances. However, these chimeric molecules will be placed in the systemic circulation and distributed to all organs, a situation in which competing, native ligands/ receptors with binding affinities equivalent to the intended therapeutic targets are abundant. Forecasting the therapeutic benefits and attendant risks of this approach is impossible. Consequently, these agents will need to be scrutinized thoroughly in animal models. Chimeric molecule dose-response issues and turnover/inactivation rates can be explored in transgenic mice, with the caveat that extrapolation to the human condition will be neither simple nor direct. In addition, efforts to detect and quantify toxic reactions in these animals will be essential. For example, the Tg2576 mice and APP23 Tg mice produce elevated Ab, but have markedly different amyloid production phenotypes that may be highly useful in assessing native ligand interference. Studies reveal that the Ab levels present in Tg2576 and APP23 mice exhibit sharply different temporal patterns. In Tg2576 mice initial Ab plasma elevation is followed by a sharp decline with concomitant accumulation in the brain, while APP23 mice immediately produce substantial soluble Ab levels in the brain followed rapidly by severe vascular amyloidosis [2, 3]. Timely treatment application may prevent consequential inflammatory side reactions resulting in the induction of vascular edema and unintended wholesale breaching of the BBB integrity. The precise status of the BBB in AD is debatable. Multiple studies confirm that a broad array of vascular pathologies is intimately associated with AD risk [4]. Although the integrity of the neurovascular BBB is widely assumed to be preserved intact until the end of life, the reality is that the BBB and cerebrovasculature, like all other tissues in the human body, suffer the degenerative effects and inevitable decay associated with aging. In a significant number of AD cases the BBB is obviously breached (permanently or transiently) as part of the syndrome, probably at the earliest stages of the disease. Furthermore, the brain is gravely affected in AD as a consequence of pathologic alterations due to massive amyloid deposition, microvascular circulation impairment due to ischemia, toxic substances, physical trauma, infection, high blood pressure, shear stress, and inflammatory reactions all of which may promote the infiltration of toxic plasma proteins. Electron microscopy on brain tissue biopsy samples from patients with mild to moderate AD has demonstrated that the integrity of the arterial walls is compromised. From a clinical and pharmacological standpoint, it seems simplistic to assume that all AD patients exhibit an equivalent vascular function status or capacity to repair age-related BBB damage. For example, evidence from clinical trials of AD immunotherapy reveals that the APOE genotype of the