Apolipoprotein E-Related Neurotoxicity as a Therapeutic Target for Alzheimer's Disease

Abstract

Apolipoprotein E (apoE) remains the most important genetic risk factor for the development of Alzheimer's disease (AD). Still elusive, the role of apoE is under intense investigation. We propose that proteolysis of apoE in the brain leads to two major fragments, N- and C-terminal apoE, each of which would drive a different neuropathological pathway. N-terminal fragments of apoE are implicated in neurotoxicity, and C-terminal fragments might play a role in amyloid deposition and plaque formation. The greater risk of AD associated with the E4 isoform might relate to its greater neurotoxicity. Drugs that either directly inhibit the toxic effects of apoE or prevent the production of apoE fragments may provide novel therapeutic approaches to the treatment of AD and other disorders in which apoE is implicated.

Apolipoprotein E e4 allele influences aggressive behaviour in Alzheimer's disease

“…Given the therapeutic opportunity to target noncognitive decline through improved understanding of ApoE neurobiology, 53 confirmation of these results is required in a longitudinal cohort followed until the late phase of AD.…”

Amino-terminal Domain Stability Mediates Apolipoprotein E Aggregation into Neurotoxic Fibrils

“…A and mediation of fibrillization and plaque formation, the binding and disruption of membranes by apoE, apoE-mediated lipid transport, and apoE-mediated neuronal sensitivity to injury and recovery [3][4][5][6][7][8][9][10][11] .…”

Apolipoprotein E-Derived Peptides Block α7 Neuronal Nicotinic Acetylcholine Receptors Expressed inXenopusOocytes

“…There are three isoforms of apoE (apoE2, apoE3, and apoE4), of which the apoE4 gene is associated with an increased risk of developing both familial and sporadic late-onset AD (Corder et al, 1993;Rebeck et al, 1993). ApoE4 has been shown to colocalize with both A␤ plaques and neurofibrillary tangles, and evidence suggests that apoE4 may be associated with the progressive loss of cognitive function in AD (for review, see Marques and Crutcher, 2003). Several hypotheses have emerged to account for apoE in the development of AD (Bales et al, 2002;Harris et al, 2003); however, none of these has yet provided a clear understanding of the role of apoE in the pathology of AD.…”