Amyloid β40/42 clearance across the blood-brain barrier following intra-ventricular injections in wild-type, apoE knock-out and human apoE3 or E4 expressing transgenic mice

An important event in the pathogenesis of Alzheimer's disease (AD) is the deposition of the amyloid beta (A beta)1-40 and 1-42 peptides in a fibrillar form, with A beta 42 typically having a greater propensity to undergo this conformational change. A major risk factor for late-onset AD is the inheritance of the apolipoprotein E (apoE) 4 allele [3,14,31]. We previously proposed that apoE may function as a "pathological chaperone" in the pathogenesis of AD (i.e. modulate the structure of A beta, promoting or stabilizing a beta-sheet conformation), prior to the discovery of this linkage [7,40-42]. Data from apoE knockout A beta PPV717F mice, , h as shown that the presence of apoE is necessary for cerebral amyloid formation [1, 2], consistent with our hypothesis. However, in A beta PPV717F mice expressing human apoE3 or E4 early A beta deposition at 9 months is suppressed, but by 15 months both human apoE expressing mice had significant fibrillar A beta deposits with the apoE4 expressing mice having a 10 fold greater amyloid burden [8,9]. This and other data has suggested that apoE, in addition to having a facilitating role in fibril formation, may also influence clearance of A beta peptides. In order to address if apoE affects the clearance of A beta peptides across the blood-brain barrier (BBB) and whether there are differences in the clearance of A beta 40 versus A beta 42, we performed stereotactic, intra-ventricular micro-injections of A beta 40, A beta 42 or control peptides in wild-type, apoE knock-out (KO) or human apoE3 or apoE4 expressing transgenic mice. We found that consistent with other studies [5], A beta 40 is rapidly cleared from the brain across the BBB; however, A beta 42 is cleared much less effectively. This clearance of exogenous A beta peptides across the BBB does not appear to be affected by apoE expression. This data suggests that A beta 42 production may favor amyloid deposition due to a reduced clearance across the BBB, compared to A beta 40. In addition, our experiments support a role of apoE as a pathological chaperone, and do not suggest an isotype specific role of apoE in exogenous A beta peptide clearance from the CSF across the BBB.