Abstract
An important event in the pathogenesis of Alzheimer's disease (AD) is the deposition of the amyloid β (Aβ)1–40 and 1–42 peptides in a fibrillar form, with Aβ42 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 Aβ, promoting or stabilizing a β-sheet conformation), prior to the discovery of this linkage [7,40,41,42]. Data from apoE knockout / AβPPV717F mice, has shown that the presence of apoE is necessary for cerebral amyloid formation [1,2], consistent with our hypothesis. However, in AβPPV717F mice expressing human apoE3 or E4 early Aβ deposition at 9 months is suppressed, but by 15 months both human apoE expressing mice had significant fibrillar Aβ 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 Aβ peptides. In order to address if apoE affects the clearance of Aβ peptides across the blood-brain barrier (BBB) and whether there are differences in the clearance of Aβ40 versus Aβ42, we performed stereotactic, intra-ventricular micro-injections of Aβ40, Aβ42 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], Aβ40 is rapidly cleared from the brain across the BBB; however, Aβ42 is cleared much less effectively. This clearance of exogenous Aβ peptides across the BBB does not appear to be affected by apoE expression. This data suggests that Aβ42 production may favor amyloid deposition due to a reduced clearance across the BBB, compared to Aβ40. 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 Aβ peptide clearance from the CSF across the BBB.