Intravascular infusions of soluble β-amyloid compromise the blood–brain barrier, activate CNS glial cells and induce peripheral hemorrhage

• Published in: Brain research 1999-02, Vol.818 (1), p.105-117
• Main Authors: Su, George C, Arendash, Gary W, Kalaria, Rajesh N, Bjugstad, Kimberly B, Mullan, Michael
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Amyloid beta-Peptides - pharmacology; Animals; Astrocytes; Biological and medical sciences; Blood-Brain Barrier - drug effects; Blood–brain barrier; Brain - blood supply; Brain - cytology; Brain - drug effects; Cerebral Hemorrhage - chemically induced; Cerebral Hemorrhage - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Glial Fibrillary Acidic Protein - analysis; Hemorrhage; Immunoglobulin G - analysis; Immunohistochemistry; Infusions, Intravenous; Male; Maze Learning - drug effects; Medical sciences; Microglia; Neuroglia - drug effects; Neurology; Rats; Rats, Sprague-Dawley; Retention (Psychology) - drug effects; Solubility; β-amyloid
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(98)01143-3

Vascular wall levels of soluble β-amyloid 1–40 (Aβ 1–40) are elevated in Alzheimer's disease (AD). Moreover, plasma Aβ levels are increased in familial AD, as well as in some cases of sporadic AD. To determine the histopathologic and behavioral consequences of elevated vascular Aβ levels, Aβ 1–40 (50 μg in distilled water) or vehicle was intravenously infused twice daily into 3-month old male Sprague–Dawley rats for 2 weeks. Intravenous Aβ infusions impaired blood–brain barrier integrity, as indicated by substantial perivascular and parenchyma IgG immunostaining within the brain. Also evident in Aβ-infused animals was an increase in GFAP immunostaining around cerebral blood vessels, and an enhancement of OX-42 microglial immunostaining in brain white matter. Gross pulmonary hemorrhage was noted in most Aβ-infused animals. All the observed changes occurred in the absence of Congo red birefringence. No significant cognitive deficits were present in Aβ-infused animals during water maze acquisition and retention testing, which was conducted during the second week of treatment. These results indicate that circulating Aβ can: (1) induce vessel dysfunction/damage in both the brain and the periphery without complex Aβ fibril formation/deposition, and (2) induce an activation of brain astrocytes and microglia. Taken together, our results suggest that if circulating Aβ is elevated in AD, it is likely to have a pathophysiologic role.