Amyloid‐β: A vascular sealant that protects against hemorrhage?

The question of whether removing amyloid-β from the brain is therapeutic has been raised again by the recent interruption of the Elan/AHP trial due to clinical signs of inflammation. The rush to find a cure for this devastating disease has resulted in the complete neglect of over 15 papers in the literature that indicate amyloid-β has properties consistent with neuroprotective functions (reviewed in Atwood et al., 2001). These properties include metal chelation, antioxidant activity, and perhaps most importantly in the present context, sealant properties that we believe are involved in maintaining the structural integrity of the blood brain barrier and parenchymal structures (Atwood et al., 1998). In keeping with the proposed role of amyloid-β as a metal chelating antioxidant and molecule involved in maintaining structural integrity under stress conditions, amyloid-β binds Cu under acidotic conditions and possesses hydrophobic and hydrophilic regions that span the plasma membrane and binds to extracellular matrix molecules (Atwood et al., 1998; Chan et al., 1999). These properties, together with its small size and ability to aggregate under inflammatory conditions makes amyloid-β an excellent candidate molecule that could form an intracranial “scab.” Cu,Zn aggregated amyloid-β would serve as a superoxide scavenging solid-phase matrix (Chan et al., 1999), which disassembles when Cu and Zn levels lower as tissue damage resolves (see Pluta et al., 1999). This may explain the acute phase generation and rapid cortical deposition of amyloid-β in stroke and following head trauma (Roberts et al., 1994), an important physiological response that would limit the loss of terminally differentiated neurons following head injury (Smith et al., 2000; Perry et al., 2000). If amyloid-β does act as a seal to maintain the integrity of the blood brain barrier, then we would expect its removal to cause leakage of serum components into the brain, resulting in an immune (or autoimmune) response characterized by inflammation. A severe consequence of such amyloid-β removal, perhaps exacerbated by inflammation, would be the occurrence of mini-strokes. Notably, this breakdown of the blood-brain barrier is consistent with the development of encephalitis and meningitis, and perhaps the presence of virus within the cerebrospinal fluid as reported in some of the patients under investigation. The adverse effects of Aβ vaccination has halted the current clinical trial, but a more balanced assessment of the current literature would have cautioned against such trials in the first place.