07 Dec 2001

Ivan Lieberburg of Elan Corporation summarized evidence over the past 15 years supporting the role of amyloid as causal in the onset and/or progression of AD. Aβ, a 42 amino acid long peptide derived the amyloid precursor protein (APP), is released from APP following β and βc-secretase cleavage, and both are aspartyl proteases that are targets for AD drug discovery, as discussed in subsequent presentations. Using the first transgenic mouse model of AD-like Aβ amyloidosis that was reported in 1995, Elan scientists discovered that immunization of young PDAPP mice with human Aβ peptides prevented the immunized mice from developing AD-like Aβ amyloid neuropathology at six months of age and beyond throughout their life span, while similar immunization of one-year-old mice with substantial Aβ amyloid neuropathology stabilized, prevented further Aβ deposition, or even reversed this pathology with advancing age for six months. These results have been repeated and extended by several other groups, and Elan scientist have gone on to show that passive immunization with some, but not all anti-Aβ antibodies yield similar therapeutic effects in these mice. Current thinking by Elan scientists is that the anti-Aβ antibodies cross the blood-brain barrier into brain, bind to Aβ fibrils in amyloid deposits and promote clearance of these plaques by brain microglia. Other groups have also shown that Aβ immunized mice with evidence of Aβ amyloid clearance learn more effectively than non-immunized transgenic mice. Elan scientists have conducted extensive toxicological testing of this immunotherapy in several mammalian species, and they have not detected evidence of toxicity, but studies in human AD and control subjects have not demonstrated any correlation between the presence or absence of anti-Aβ antibodies or levels thereof with the disease state. However, Elan scientists have completed two phase 1 clinical trials of this immunotherapy in the USA and the UK, and they now have initiated a multisite phase 2 study in 375 mild to moderate AD patients.—John Trojanowski