Henry M. Wisniewski M.D. Ph.D.
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Journal Article↗
Biomedical subjects
Thomas Wisniewski
Publications and source records attributed to Thomas Wisniewski.
Amyloid beta40/42 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 (Abeta)1-40 and 1-42 peptides in a fibrillar form, with Abeta42 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 Abeta, promoting or stabilizing a beta-sheet conformation), prior to the discovery of this linkage [7,40,41,42]. Data from apoE knockout / AbetaPP^(V717F) mice, has shown that the presence of apoE is necessary for cerebral amyloid formation [1,2], consistent with our hypothesis. However, in betaPP^(V717F) mice expressing human apoE3 or E4 early Abeta deposition at 9 months is suppressed, but by 15 months both human apoE expressing mice had significant fibrillar Abeta 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 Abeta peptides. In order to address if apoE affects the clearance of Abeta peptides across the blood-brain barrier (BBB) and whether there are differences in the clearance of Abeta40 versus Abeta42, we performed stereotactic, intra-ventricular micro-injections of Abeta40, Abeta42 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], Abeta40 is rapidly cleared from the brain across the BBB; however, Abeta42 is cleared much less effectively. This clearance of exogenous Abeta peptides across the BBB does not appear to be affected by apoE expression. This data suggests that Abeta42 production may favor amyloid deposition due to a reduced clearance across the BBB, compared to Abeta40. 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 Abeta peptide clearance from the CSF across the BBB.
Journal Article↗
A safer vaccine for Alzheimer's disease?
Recent reports indicate that amyloid-beta (Abeta) vaccine-based therapy for Alzheimer's disease (AD) may be on the horizon. There are, however, concerns about the safety of this approach. Immunization with Abeta1-42 may not be appropriate in humans because it crosses the blood-brain barrier, can seed fibril formation, and is highly fibrillogenic. Abeta1-42 fibrils can in turn cause inflammation and neurotoxicity. This issue is of a particular concern in the elderly who often do not mount an adequate immune response to vaccines. Our findings show that vaccination with nonamyloidogenic/nontoxic Abeta derivative may be a safer therapeutic approach to impede the progression of Abeta-related histopathology in AD. Although the site of action of the anti-Abeta antibodies has been suggested to be within the brain, peripheral clearance of Abeta may have a greater role in reducing cerebral amyloid plaques in these animals and eventually in AD patients. Antibodies in general are predominantly found outside the central nervous system (CNS) and will, therefore, primarily clear systemic Abeta compared to brain Abeta. This disruption of the equilibrium between central and peripheral Abeta should then result in efflux of Abeta out of the brain, and subsequent removal of plaques. Abeta therapy can be targeted to the periphery, which may result in fewer CNS side effects, such as inflammation. Future Abeta derived vaccines should include T(h) epitopes, carriers and/or lipid moieties to enhance antibody production in the elderly, the population predominantly affected by AD.
Alzheimer Disease↗