Proteolytic Cleavage of Apolipoprotein E4 as the Keystone for the Heightened Risk Associated with Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by microscopic lesions consisting of beta-amyloid plaques and neurofibrillary tangles (NFTs). The majority of cases are defined as sporadic and are likely caused by a combination of both genetic and environmental factors. Of the genetic risk factors identified, the 34 kDa protein, apolipoprotein (apo) E4, is of significant importance as APOE4 carriers account for 65%–80% of all AD cases. Although apoE4 plays a normal role in lipoprotein transport, how it contributes to AD pathogenesis is currently unknown. One potential mechanism by which apoE4 contributes to disease risk is its propensity to undergo proteolytic cleavage generating N- and C-terminal fragments. The purpose of this review will be to examine the mechanisms by which apoE4 contributes to AD pathogenesis focusing on the potential loss or gain of function that may occur following cleavage of the full-length protein. In this context, a discussion of whether targeting apoE4 therapeutically is a rationale approach to treating this disease will be assessed.

Dissecting the Contribution of Vascular Alterations and Aging to Alzheimer’s Disease

“…The sporadic form of AD seems to be related to several genetic and environmental factors [7]. A major contributing gene to sporadic late-onset AD is APOE, encoding apolipoprotein E, since as many as 65-80 % of all AD patients are carriers of the APOE ε4 allele (APOE4) [8]. In addition, several other susceptibility loci have been identified in a meta-analysis of genome-wide association studies in individuals of European ancestry, although these are potentially not the causative genes but instead can enhance the risk of AD [9].…”

The Role of Alzheimer’s and Cerebrovascular Pathology in Mediating the Effects of Age, Race, and Apolipoprotein E Genotype on Dementia Severity in Pathologically-Confirmed Alzheimer’s Disease

“…Possession of the APOE ε 4 allele is the most common genetic risk factor for sporadic AD, with risk of disease increasing fourfold or tenfold with inheritance of one or two copies of the allele, respectively [33,34]. The ε 4 allele is most reliably linked to AD through its action on the deposition and accumulation of A β plaques, but other pathogenetic mechanisms, including atrophy, tau phosphorylation, lipid metabolism, synaptic plasticity, inflammation, and neurogenesis, are also linked to this allele [35].…”

Is There Any Relationship between Apolipoprotein E Polymorphism and Idiopathic Parkinson’s Disease?

“…The other theory is that proteolytically cleaved apoE4 can do major role in the development of Alzheimer's disease. A fragment of apoE4 was found in the pathologies of Alzheimer's disease which is indicative of a toxic effect of apoE4 on the disease [9]. Lastly, apoE4 may cause neurotoxicity by mitochondrial dysfunction and formation of neurofibrillary tangles supposed by an animal study [10].…”