Distribution of intraventricularly administered antiamyloid‐beta peptide (Aβ) antibody in the mouse brain

Abstract

There is considerable interest in utilizing the intracerebroventricular (icv) route of administration of antibodies in the brain for various studies and for the therapy of malignancies, but very little is known about the anatomic extent of distribution of the antibody in brain after injection into the third ventricle. To explore the potential for icv administration of antiamyloid-beta peptide (Abeta) in reducing Abeta toxicity in brain in Alzheimer's disease, we first mapped the time course and path of transit of horseradish peroxidase (HRP)-labeled antibody. The results show that, after a single injection into the mouse third venticle, the HRP-labeled antibody is localized within the microvasculature, first that of the corticohippocampal region close to the site of injection at 3 hr. By 24 hr, the antibody is distributed throughout the hippocampus and frontoparietal cortex close to the injection site, as well as in the deep and outer cerebral cortex and cerebellar cortex remote from the injection site. The injected antibody is almost entirely removed by 4 days. Therefore, the antibody had diffused throughout all the brain by 24 hr, showing the feasibility of small quantities of anti-Abeta antibody infused into the third ventricle to reach extracellular epitopes throughout the brain parenchyma rapidly.

Antibody Buffering in the Brain

“…They are not restricted to regions around the ventricles or the surfaces of the brain, but diffuse throughout the brain. Chauhan et al 3 showed that 3 h after injection of a horseradish peroxidase conjugated antibody into the third ventricle of the mouse brain, the antibody was localized mainly near the injection site. After 24 h, however, the antibody had diffused throughout the brain parenchyma, while at four days post-injection only a few traces of antibody remained anywhere in the brain.…”

Intracerebroventricular amyloid-β antibodies reduce cerebral amyloid angiopathy and associated micro-hemorrhages in aged Tg2576 mice

“…Given the likelihood that immunotherapy-solubilized amyloid redistributes from the parenchymal plaques to the cerebral vasculature (19,21,47), it is possible that the amyloid clearance from prolonged icv infusions of low-dose anti-A␤ antibodies is sufficiently gradual that it fails to substantially accumulate in the cerebral vasculature and result in CAA. We aimed to test this hypothesis by delivering bolus icv injections of relatively high doses of anti-A␤ antibodies to briefly flood the CSF and maximize the movement of antibody into the parenchyma for clearance of amyloid (48,49). Aged Tg2576 mice received a single icv injection of 6E10 at a dose (0.5 g) calculated to acutely provide an antibody concentration in the CSF equivalent to that maintained during the prolonged infusion study.…”

The chalcone derivative Chana 1 protects against amyloid�β peptide-induced oxidative stress and cognitive impairment

“…Chana 1 was dissolved in tap water and orally administered daily for 34 days. After administration of Chana 1 or control drugs for 28 days, Aβ or Aβ 42-1 was administered by intracerebroventricular injection (410 pmol per mouse) according to Chauhan's method (24). The control group was injected with Aβ 42-1 , the non-toxic reverse fragment.…”