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.

Figure 1

The amino terminal fragment of apolipoprotein (apo) E4 (apoE4) localizes to neurofibrillary tangles (NFTs) in the Alzheimer’s disease (AD) brain. (A) Representative bright field microscopy image from frontal cortex AD brain sections utilizing anti-Aβ antibody, clone 6E10 (blue-black) together with a custom synthesized antibody that specifically detects the amino terminal fragment of apoE4 (brown) revealed specific localization of this fragment within NFTs, in this case near an extracellular plaque labeled with an anti-Aβ antibody (arrow); (B) Double-label immunofluorescence using paired helical filaments (PHF-1) (red) as a marker for NFTs and the custom antibody to the amino terminal fragment of apoE4 (green) showed strong colocalization (yellow) in a subset of tangles in the AD brain (arrow). Scale bars are 10 μm for (A) and 20 μm for (B).

Figure 2

Proteolysis of apoE4 leads to a gain of function. The figure summarizes key features associated with AD including the formation of beta-amyloid by beta/gamma secretase and the deposition into extracellular plaques as well as formation of NFTs. A revision of the beta-amyloid hypothesis, as it has become known, is the role that oligomeric forms of beta-amyloid may play in disease progression. Thus, beta-amyloid oligomers now are thought to represent the cytotoxic species that can confer synapse loss, oxidative stress and neuronal damage. A key step in this process is mitochondrial disruption by beta-amyloid oligomers that may lead to the activation of apoptotic pathways in the AD brain. ApoE4 may promote the pathogenesis underlying AD following cleavage and generation of an N-terminal fragment. This fragment in turn may lead to a toxic gain of function of apoE4 in three ways: (1) Disruption of mitochondrial function by impairment of enzymes involved in the respiratory chain complex; (2) Promotion on the intracellular accumulation of beta-amyloid by stimulating cellular uptake; (3) induce tangle-like inclusions resembling neurofibrillary tangles. The cumulative end results of these processes may lead to enhanced pathology, neuronal deficits in memory and learning, and neurodegeneration. See main text for details.

Figure 3

Proteolysis of apoE4 leads to a loss of normal function. Following cleavage of apoE4 by as yet an unidentified protease, could hypothetically lead to a loss of function of apoE4; including: (1) Impairment of cholesterol transport. In the CNS, apoE is one of the major lipid acceptors and functions to shuttle cholesterol to and from cells to generate high-density lipoprotein (HDL) particles. Loss of this function could deplete HDL-cholesterol that is essential for synaptogenesis and neurite outgrowth in neurons and thereby limit the recovery from neurodegeneration observed in AD; (2) AD is associated with impaired clearance of beta-amyloid from the brain, a process that is normally facilitated by apoE. In this regard, apoE4 is known to bind directly to oligomeric beta-amyloid enhancing its clearance out of the CNS and although it does this very poorly as compared to apoE2 and apoE3, proteolytic cleavage could further exacerbate this important role in individuals harboring the apoE4 allele in AD.