Rhinn H, Fujita R, Qiang L, Cheng R, Lee JH, Abeliovich A.
Integrative genomics identifies APOE ε4 effectors in Alzheimer's disease.
Nature. 2013 Aug 1;500(7460):45-50.
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Apart from aging itself, apolipoprotein E (Apo-E) polymorphic alleles are the primary genetic determinants of risk for sporadic late onset Alzheimer disease (LOAD). Rhinn et al. have uncovered a candidate effector pathway for Apo-E4 on amyloid beta precursor protein (APP) endocytosis and metabolism contributing to LOAD. In addition to advancing biological understanding, the report has potential therapeutic implications in support of Sv2a as a target to prevent LOAD, at least in ApoE4 carriers. Would the Sv2a inhibitor used to suppress altered APP processing in APOE4-positive human induced neurons (hiNs) have in vivo efficacy in that population?
While that remains to be seen, it is important to note that targeting Sv2a has shown beneficial effects in aging, MCI patients, and AD models apart from ApoE4. This is true for our (Bakker et al., 2012) and a second prior study using levetiracetam cited by the authors (Sanchez et al., 2012).
The AD mouse model used by Sanchez et al. is devoid of ApoE4 but showed improved cellular, network, and behavioral outcomes specific for mice with hAPP overexpression after treatment with the Sv2a ligand levetiracetam (see also Spiegel et al., 2013 for further evidence of a therapeutic benefit in a rodent model, absent ApoE4). Hyperactivity leading to network dysfunction is a common feature of these preclinical models. As Rhinn and colleagues noted, our report using low dose levetiracetam in amnestic mild cognitive impairment (MCI) ascribed therapeutic benefit to effective reduction of hippocampal hyperactivity. We have since completed additional cohorts of MCI patients under the same protocol (totaling N=54). In the aggregate MCI study population, 43 percent of the genotyped subjects were APOE4 carriers. The signature of hyperactivity localized within the hippocampal formation was not restricted to APOE4 carriers but was evident in carriers and non-carriers alike. The notion that this condition contributes to disease progression is supported by a close association between the magnitude of hippocampal hyperactivity in MCI with the severity of structural atrophy in key AD related areas of the brain (Putcha et al., 2011). It is also notable that hippocampal hyperactivity is seen pre-symptomatically in early-onset AD (Quiroz et al., 2010) as well as in asymptomatic APOE4 carriers and in aMCI, irrespective of E4 carrier status. Hence, drugs that target Sv2a could be beneficial therapeutically in the broader context of prodromal AD, while not being limited to the ApoE4 population.
Bakker A, Krauss GL, Albert MS, Speck CL, Jones LR, Stark CE, Yassa MA, Bassett SS, Shelton AL, Gallagher M.
Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment.
Neuron. 2012 May 10;74(3):467-74.
Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Ho K, Yu GQ, Palop JJ, Mucke L.
Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model.
Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):E2895-903.
Spiegel AM, Koh MT, Vogt NM, Rapp PR, Gallagher M.
Hilar interneuron vulnerability distinguishes aged rats with memory impairment.
J Comp Neurol. 2013 Jun 8;
Putcha D, Brickhouse M, O'keefe K, Sullivan C, Rentz D, Marshall G, Dickerson B, Sperling R.
Hippocampal hyperactivation associated with cortical thinning in Alzheimer's disease signature regions in non-demented elderly adults.
J Neurosci. 2011 Nov 30;31(48):17680-8.
Quiroz YT, Budson AE, Celone K, Ruiz A, Newmark R, Castrillón G, Lopera F, Stern CE.
Hippocampal hyperactivation in presymptomatic familial Alzheimer's disease.
Ann Neurol. 2010 Dec;68(6):865-75.
The data jibe well with longstanding human and mouse data showing that APOE4 enhances brain amyloid pathology robustly (especially cerebral amyloid angiopathy). It is heartening to think that after 20 years of APOE4 linkage to AD, there are new exciting leads that might, at long last, offer an explanation, especially since APOE4 is present in about 50 percent of patients with AD and is the most common identified genetic risk for the disease. The claim that APOE isotype-specific modulation of the expression of protein sorting genes can be demonstrated using patient-specific iPS cell technology certainly comports well with the generally agreed concept that APP sorting—specifically endosomal residence time—plays a critical role in amyloid β generation.
I have some serious concerns about this paper, however:
First, overexpression of APOE4 vs APOE3 cDNAs in cultured cells does not typically change APP sorting or Aβ biogenesis. This has been tested before by Selkoe and Younkin (see Biere et al., 1995) and by others, including our lab.
Second, some of the genes that the authors link to APOE4 have been linked to AD and have been shown to regulate APP processing and Aβ biogenesis but those actions have been associated with either missense mutations or polymorphisms that appear to act by modulating gene expression. APOE4 was not required to reveal the effects of the mutations/polymorphisms on APP processing and Aβ biogenesis in cells nor has APOE4 been required for the mutations/linkages to exert effects on disease risk.
The conventional wisdom on the likely mechanism of APOE4’s effects on AD pathogenesis favors APOE-isotype-specific modulation of Aβ clearance. Randy Bateman’s in vivo human data support this model (see ARF related news story). One conceivable (albeit unlikely) scenario that would unify the existing data is that the APOE4-misregulated genes that the authors report are not only APP missorting genes but also function in the uptake and clearance of secreted Aβ. This possibility remains to be tested.
Third and lastly, the use of recombinant ApoE also raises a red flag. Only astrocytes express and lipidate ApoE and package it into discs and particles in a brain-relevant physiological fashion. Biovision recombinant ApoE is produced in bacteria and lyophilized. Apolipoproteins are extraordinarily difficult reagents to generate and handle properly. Many cell biologists would say that the only physiologically relevant ApoE currently employed in brain and AD research is that recovered from the conditioned media of David Holtzman's immortalized APOE-isotype-expressing astrocytes. Bacterially expressed, unlipidated, lyophilized ApoE is about as far from physiologically relevant as the chloroform: methanol extracted and purified material that has been responsible for two decades worth of artifacts in the literature.
Biere AL, Ostaszewski B, Zhao H, Gillespie S, Younkin SG, Selkoe DJ.
Co-expression of beta-amyloid precursor protein (betaAPP) and apolipoprotein E in cell culture: analysis of betaAPP processing.
Neurobiol Dis. 1995 Jun;2(3):177-87.
Rhinn and colleagues report in this very interesting paper similar differential gene regulation in disease-free APOE4 carriers and non-APOE4 late onset Alzheimer’s disease (AD) patients, using differential co-expression analysis. The overlap in gene expression identified a number of modifiers of APP processing and transport, including SV2A and RNF219, which has not been linked to AD before. The authors move on to show in cell culture that both SV2A and RNF219 regulate the release of Aβ from human APP- expressing cells in an APOE4-dependent manner. Amongst the identified genes was also FYN, which we linked to Aβ toxicity and tau in our previous work (Ittner et al., 2010).
However, whether the modulation of Aβ pathology in the context of APOE4 also involves tau remains to be seen. Interestingly, the gene profile analysis suggests there are independent mechanisms at play in APOE4-positive late-onset AD and age-related late-onset AD. It will be interesting to see if the function of SV2A and RNF219 described here in cell culture can be reproduced in AD animal models, though there is already supporting evidence from AD mouse studies for SV2A, a target of levetriacetam.
Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wölfing H, Chieng BC, Christie MJ, Napier IA, Eckert A, Staufenbiel M, Hardeman E, Götz J.
Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models.
Cell. 2010 Aug 6;142(3):387-97.