Chiang GC, Insel PS, Tosun D, Schuff N, Truran-Sacrey D, Raptentsetsang ST, Jack CR, Aisen PS, Petersen RC, Weiner MW, .
Hippocampal atrophy rates and CSF biomarkers in elderly APOE2 normal subjects.
Neurology. 2010 Nov 30;75(22):1976-81.
Please login to recommend the paper.
To make a comment you must login or register.
This new work from Chiang et al. is important because it emphasizes our lack of understanding regarding the neuroprotective roles of ApoE2. For years, researchers have tried to establish the link between E4 carriers or non-carriers and brain region-specific neuronal loss, particularly in a diseased state. Thus, understanding the contribution of ApoE genotype to brain atrophy in the presence and absence of neurodegenerative pathology is not novel. However, previous research has primarily centered on the E3 versus E4 alleles, with little attention paid to individuals harboring E2 (albeit largely due to the rarity of elderly E2 carriers). Chiang not only found a decreased rate of hippocampal atrophy in the presence of ApoE2, but an increase in CSF Aβ levels.
Although these results are suggestive, their interpretation is limited because the distinction between Aβ42 versus Aβ40 or other species was not made. In addition, the human cohort analyzed by Chiang et al. spanned 35 years and contained only 17 E2 participants for the biomarker analyses. Although this is understandable, it is important for researchers to know the subdivision of ages as they relate to ApoE isoform. This would allow us to determine whether the results were skewed due to a predominance of younger (i.e., healthier) individuals with an E2 allele, as older individuals would reasonably be expected to show both increased rates of atrophy and decreased Aβ clearance. In our lab’s new mouse model of Aβ pathology, ApoE has no isoform-specific effects on brain Aβ40 levels but does alter Aβ42 levels and solubility. Importantly, mice homozygous for ApoE4 have increased levels of soluble Aβ42, while levels remain low with ApoE2. This suggests an increased clearance of soluble Aβ42 out of the brain parenchyma in the presence of ApoE2 that does not occur, or is impaired, with ApoE4. Chiang’s recent findings support our theory. Additional data from our lab indicate that both ApoE2 and ApoE4 correlate with increased Aβ42 accumulation, although ApoE2 may alter the nature of Aβ42 deposition toward diffuse versus compact amyloid, particularly in disease-vulnerable regions. Substantial Aβ pathology has also been observed in E2 carriers older than 90 years of age, further supporting our hypothesis and suggesting that the clearance of Aβ42 into the CSF may ultimately depend on the body’s ability to break up and remove various conformational species of the peptide, which could vary significantly with age and ApoE genotype. Hopefully, the data from our and Chiang’s labs regarding the pathological effects of ApoE2 will articulate to others the need for comprehensive analyses that include all three isoforms of ApoE, if we are to understand the mechanism(s) underlying the onset and progression of AD pathology.
It is not surprising at all that there is a difference in the "hippocampal atrophy rates and less AD pathology in CSF of ApoE2 carriers (relative to E3/E3 participants) from the ADNI cohort of cognitively normal individuals." The critical contributing factors to the progression of disease is the ApoE isoform/Tomm40 interaction rates. ApoE2 contains two sulfhydryl groups, while ApoE3 contains one, and none on ApoE4. Huang and colleagues have demonstrated exquisite evidence of the facts that were not believed in the 1990s—that ApoE is expressed in the neuronal cytoplasm, that the terminal 20 amino acids are cleaved, allowing ApoE(1-272) to bind to the outer mitochondrial membrane at the Tomm40 site (see Chang et al., 2005). The degree of binding is ApoE4>ApoE3, with no binding of ApoE2 due to a change of secondary protein structure with two cysteine groups replacing two arginines. Compared to ApoE3[1-272), the binding of ApoE4(1-272) causes decreased mitochondrial dynamics [(speed and distance moved). ApoE2 has no (273-299] cleavage and presumably has no effect on mitochondrial dynamics. Thus two APOE3 alleles is worse than one APOE3 and one APOE2 allele.
From our current view of the pathophysiology of AD and its relationship to the TOMM40 Rs10524523 nucleotide polymorphism and APOE genotypes that are inherited together throughout evolution, the age of onset appears to be determined by the TOMM40 Rs10524523 variable polyT polymorphisms on each DNA strand. APOE2 is known to be derived from APOE3 strands. It is too early to say in Caucasians, but we have data to demonstrate that APOE2 is connected to the very long form (523 VL) of Tomm40 in both Caucasians and African populations. Studies are ongoing to assess the proportion of 523-VL, versus 523-Short, that predict an earlier age of onset compared to the age of onset curves for the APOE3/3 homozygotes: VL/VL and S/S. Preliminary evidence shows that when an APOE2/3 patient develops AD, the VL polymorphisms predominate. With many more APOE2/3 carriers we will be able to construct age of onset distributions for this generally later group of patients. To date, we have demonstrated that 523-VL/APOE2 is enriched in AD patients compared to 523-S/APOE2 carriers. This is now still a hypothesis but it is consistent with the viewpoint and data in hand. Damaged mitochondrial undergo an apoptotic process, releasing cytochrome c, which stimulates the caspase pathways. This can be viewed as turning on the "so-called" amyloid cascade with the proximal problem being slow toxicity of the mitochondria over years. How 523 affects expressed Tomm40 channel protein is currently also under study. In yeast and other genomes, intronic polyT variants can affect the expression levels, with an increase in number leading to progressive decreases in protein expression relative to other genes. It is also possible that VL polyTs can lead to alternative splicing, thus changing the sequence of the Tom40 channel as well.
From this point of view, the report from ADNI is consistent, at least in this important location, with the current data available about the etiological process underlying AD.
Chang S, ran Ma T, Miranda RD, Balestra ME, Mahley RW, Huang Y.
Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity.
Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18694-9.