Tag Archives: APOE

Reconciling conflicting results in Alzheimer’s disease research

VerghesevCarloAmyloid beta (Aß) deposition is a hallmark pathology in Alzheimer’s disease (AD). The apolipoprotein E (ApoE) gene, which encodes for the ApoE protein, has been established as a strong influence for the development of late-onset AD(1). The link between ApoE and Aß is unclear. One theory postulates that ApoE directly binds with Aß to mediate Aß clearance(2-4), while a second theory suggests the effects of ApoE on Aß clearance are indirect(5-7). Recent papers by Carlo et al(8) and Verghese et al(9) support these two respective contradicting theories.

In line with the first theory of a direct interaction between ApoE and Aß, Carlo et al found that sortilin, and not low-density lipoprotein receptor-related protein 1 (LRP1), mediates the cellular uptake of Aß/ApoE complexes, suggesting that sortilin is a major ApoE receptor that is essential for Aß clearance(8). In contrast, Verghese et al demonstrated that ApoE and Aß rarely bind together and that ApoE competes with Aß to bind with LRP1(9), which plays a role in neuronal Aß uptake(10). Thus, Verghese et al’s results suggest that ApoE inhibits Aß clearance via binding to LRP1(9). Verghese et al’s findings therefore are in accordance with the second theory that ApoE indirectly affects Aß clearance.

It would appear as though the experiments done by Carlo et al and Verghese et al are in contradiction with each other. However, there are important differences between these studies that may contribute to their contrasting results. First, Carlo et al examined the effects of sortilin and LRP1 on Aß/ApoE complexes, while Verghese et al did not use Aß/ApoE complexes in their experiments with LRP1. This might indicate that LRP1 is capable of binding to Aß only when it is not bound to ApoE. While there is an overwhelming amount of evidence that shows a direct interaction between ApoE and Aß(11-16), which supports Carlo et al, Verghese et al pointed out that the majority of studies demonstrating Aß/ApoE binding used synthetically prepared Aß at above physiological concentrations and did not assess the mechanisms behind the effects of Aß/ApoE complexes on Aß metabolism9. Verghese et al challenges previous literature as they show that Aß and ApoE rarely bind together under physiological conditions yet ApoE continues to affect Aß clearance, suggesting that the primary role of ApoE in Aß clearance is unlikely due to ApoE sequestering Aß. This implies that the two groups examined different pathways of ApoE-related Aß clearance: one pathway that depends on Aß/ApoE complexes and one that does not. Thus, the results from the two groups do not necessarily oppose each other as they targeted different pathways that may both contribute to Aß clearance, but the question remains as to which pathway contributes the most to Aß clearance.

In order to reconcile the results from Carlo et al and Verghese et al, several experiments could be done. Aß uptake should be measured in sortilin-expressing, sortilin-deficient, LRP1-expressing, and LRP1- deficient cells incubated with soluble Aß only, soluble Aß with ApoE (with molar ratios in the physiological range, as previously described(9)), and Aß complexed with ApoE (as previously described(8)). This would enable us to determine how free ApoE and Aß-bound ApoE influence Aß clearance with and without sortilin and LRP1. This would also enable us to see whether sortilin is capable of clearing Aß when it is not complexed with ApoE and conversely, whether LRP1 is capable of clearing Aß when complexed with ApoE. These experiments may clarify which pathway has the largest influence on Aß clearance. ApoE expression can be controlled by LXRs(17). Therefore, upregulating and downregulating the expression of ApoE with LXR agonists and antagonists in amyloid mouse models to examine the effects on Aß clearance may also be useful. If Aß clearance is increased by ApoE upregulation, then that would support Carlo et al’s finding that ApoE binding to Aß is essential for the latter’s clearance. If Aß clearance is increased by ApoE downregulation, then that would support Verghese et al’s finding that ApoE inhibits Aß clearance. In fact, there have been conflicting results regarding the effects of increasing or decreasing ApoE expression, as upregulating ApoE has been shown to facilitate Aß clearance(18), yet reduced ApoE expression may reduce Aß levels(19). Therefore, modifying ApoE expression in sortilin-expressing, sortilin knock-outs, LRP1- expressing, and LRP1-knock-outs crossed with amyloid mice could also be done to see how these receptors impact Aß clearance depending on the level of ApoE expression.


1 Poirier, J. et al. Apolipoprotein E polymorphism and Alzheimer’s disease. Lancet 342, 697-699, doi:0140-6736(93)91705-Q [pii] (1993).

2 Koistinaho, M. et al. Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat Med 10, 719-726, doi:10.1038/nm1058nm1058 [pii] (2004).

3 Morikawa, M. et al. Production and characterization of astrocyte-derived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-beta. Neurobiol Dis 19, 66-76, doi:S0969-9961(04)00279-7 [pii]10.1016/j.nbd.2004.11.005 (2005).

4 Jiang, Q. et al. ApoE promotes the proteolytic degradation of Abeta. Neuron 58, 681- 693, doi:10.1016/j.neuron.2008.04.010S0896-6273(08)00328-0 [pii] (2008). 5 Kim, J. et al. Overexpression of low-density lipoprotein receptor in the brain

markedly inhibits amyloid deposition and increases extracellular A beta clearance. Neuron 64, 632-644, doi:10.1016/j.neuron.2009.11.013S0896-6273(09)00896-4 [pii] (2009).

6 Basak, J. M., Verghese, P. B., Yoon, H., Kim, J. & Holtzman, D. M. Low-density lipoprotein receptor represents an apolipoprotein E-independent pathway of Abeta uptake and degradation by astrocytes. J Biol Chem 287, 13959-13971, doi:10.1074/jbc.M111.288746M111.288746 [pii] (2012).

7 Katsouri, L. & Georgopoulos, S. Lack of LDL receptor enhances amyloid deposition and decreases glial response in an Alzheimer’s disease mouse model. PLoS One 6, e21880, doi:10.1371/journal.pone.0021880PONE-D-11-05741 [pii] (2011).

8 Carlo, A. S. et al. The pro-neurotrophin receptor sortilin is a major neuronal apolipoprotein E receptor for catabolism of amyloid-beta peptide in the brain. J Neurosci 33, 358-370, doi:10.1523/JNEUROSCI.2425-12.201333/1/358 [pii] (2013).

9 V erghese, P . B. et al. ApoE influences amyloid-beta (Abeta) clearance despite minimal apoE/Abeta association in physiological conditions. Proc Natl Acad Sci U S A 110, E1807-1816, doi:10.1073/pnas.12204841101220484110 [pii] (2013).

10 Kanekiyo, T. et al. Heparan sulphate proteoglycan and the low-density lipoprotein receptor-related protein 1 constitute major pathways for neuronal amyloid-beta uptake. J Neurosci 31, 1644-1651, doi:10.1523/JNEUROSCI.5491-10.201131/5/1644 [pii] (2011).

11 Namba, Y., Tomonaga, M., Kawasaki, H., Otomo, E. & Ikeda, K. Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer’s disease and kuru plaque amyloid in Creutzfeldt-Jakob disease. Brain Res 541, 163-166, doi:0006-8993(91)91092-F [pii] (1991).

12 Strittmatter, W. J. et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 90, 1977-1981 (1993).

13 Bales, K. R. et al. Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 96, 15233-15238 (1999).

14 LaDu, M. J. et al. Isoform-specific binding of apolipoprotein E to beta-amyloid. J Biol Chem 269, 23403-23406 (1994).

NEUR 602: Carlo et al vs Verghese et al Angela Tam

15 Yang, D. S., Smith, J. D., Zhou, Z., Gandy, S. E. & Martins, R. N. Characterization of the binding of amyloid-beta peptide to cell culture-derived native apolipoprotein E2, E3, and E4 isoforms and to isoforms from human plasma. J Neurochem 68, 721- 725 (1997).

16 Kim, J., Basak, J. M. & Holtzman, D. M. The role of apolipoprotein E in Alzheimer’s disease. Neuron 63, 287-303, doi:10.1016/j.neuron.2009.06.026S0896- 6273(09)00549-2 [pii] (2009).

17 Laffitte, B. A. et al. LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc Natl Acad Sci U S A 98, 507-512, doi:10.1073/pnas.021488798021488798 [pii] (2001).

18 Riddell, D. R. et al. The LXR agonist TO901317 selectively lowers hippocampal Abeta42 and improves memory in the Tg2576 mouse model of Alzheimer’s disease. Mol Cell Neurosci 34, 621-628, doi:S1044-7431(07)00021-8 [pii]10.1016/j.mcn.2007.01.011 (2007).

19 Bien-Ly, N., Gillespie, A. K., Walker, D., Yoon, S. Y. & Huang, Y. Reducing human apolipoprotein E levels attenuates age-dependent Abeta accumulation in mutant human amyloid precursor protein transgenic mice. J Neurosci 32, 4803-4811, doi:10.1523/JNEUROSCI.0033-12.201232/14/4803 [pii] (2012).

Q&A: Early-onset vs. late-onset Alzheimer’s disease

Alzheimer’s disease (AD) is typically split into two subgroups: early-onset and late-onset.  Early-onset AD is diagnosed in people whose symptoms began to appear before the age of 60, sometimes appearing as early as their 30s or 40s.  Late-onset AD is diagnosed in those whose symptoms appear after the age of 60.

Fingerprint is the past. Breathprint is the future?

The single greatest known risk factor for AD is actually increasing age.  The risk of getting AD doubles every 5 years after the age of 65, to the point where people over 85 have a 50% chance of having dementia.  Consequently, the majority (over 90%) of all AD cases are of the late-onset type.  Aside from age, a second known risk factor for AD is linked to a gene called the apolipoprotein E (APOE) gene.  The APOE gene contains instructions on coding for a protein called APOE, which helps transport cholesterol and other fats in the bloodstream.  There are three common allelic variations of the APOE gene: APOE ε2, APOE ε3, and APOE ε4.  The presence of the APOE ε4 gene increases one’s risk of developing AD but will not guarantee the incidence of the disease.  The APOE ε4 gene is present in about a quarter to a third of the general population – this proportion increases to 40% in patients with late-onset AD.

New Class of RNA: Circular RNA

In comparison to late-onset AD, early-onset AD has a very strong genetic component.  This is sometimes called familial AD.  It is currently known that mutations in the following three genes cause early-onset AD: amyloid precursor protein (APP), presenilin-1, and presenilin-2.  Early-onset AD is an autosomal dominant genetic disease.  This means that a person requires only one copy of the mutated gene, passed on by either the mother or the father, to inherit the disease.  This also unfortunately means that people with mutations in these genes will certainly develop AD.

Related: What’s the difference between dementia and Alzheimer’s?

For further reading, check out the references below:

  1. NIH – National Institute on Aging: AD Genetics Fact Sheet
  2. Alzheimer’s Association: AD & Dementia Risk Factors
  3. Kowalska A. Amyloid precursor protein gene mutations responsible for early-onset autosomal dominant Alzheimer’s Disease. Folia Neuropathol. 2003;41(1):35-40. [abstract]
  4. Campion D et al. Mutations of the presenilin I gene in families with early-onset Alzheimer’s disease. Hum. Mol. Genet. (1995) 4 (12):2373-2377.  doi: 10.1093/hmg/4.12.2373 [abstract]
  5. Cruts M et al. Estimation of the Genetic Contribution of Presenilin-1 and -2 Mutations in a Population-Based Study of Presenile Alzheimer Disease. Hum. Mol. Genet. (1998) 7 (1):43-51.  doi: 10.1093/hmg/7.1.43 [full text]