Kramer PL, Xu H, Woltjer RL, Westaway SK, Clark D, Erten-Lyons D, Kaye JA, Welsh-Bohmer KA, Troncoso JC, Markesbery WR, Petersen RC, Turner RS, Kukull WA, Bennett DA, Galasko D, Morris JC, Ott J.
Alzheimer disease pathology in cognitively healthy elderly: a genome-wide study.
Neurobiol Aging. 2011 Dec;32(12):2113-22.
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Being well aware of the small sample size and the requirement for further experimental confirmation, I find the focus and approach of this GWAS very interesting because it addresses for the first time genetic differences related to AD neuropathology in clinically non-demented elderly. This is very important, since a considerable proportion of subjects involved in cross-sectional control studies for AD might may indeed harbor genetic variants that predispose them to develop AD. One of these putative risk factors appears to be strongly associated with the RELN locus, the gene encoding for the extracellular matrix protein reelin. The authors found a strong association between RELN gene variants and AD neuropathology. However, at this stage we do not know yet whether, and how, these polymorphisms affect reelin signaling pathways in adult synapses. The authors observe an increase in reelin immunoreactivity in CA2/CA3 pyramidal neurons in the postmortem tissue obtained from individuals with high as compared to low AD pathology. This was very similar to the situation in AD patients with dementia, where reelin immunoreactivity was particularly evident in brain areas with high granulovacuolar degeneration.
The authors' interpretation was that a putative upregulation of reelin might compensate for tau- and Aβ-associated cellular stress, potentially sustaining the cognitive reserve in these individuals. Although this hypothesis is very attractive, we do not have any information on the mRNA levels to confirm this. There is also a debate as to whether this intraneuronal reelin immunoreactivity in primates and humans is related to receptor-mediated endocytosis, since in rodents CA pyramidal cells do not express reelin. Therefore, more investigations are required to identify the molecular explanation for the increase in reelin immunoreactivity in CA2/3 pyramidal neurons described in high AD neuropathology subjects.
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by three major pathological hallmarks: senile plaques, neurofibrillary tangles (NFTs), and neurodegeneration. This pathology is believed to underlie the debilitating cognitive dysfunction associated with AD. When defining AD on the basis of these pathological attributes, a singular contradiction emerges; it is possible to have significant brain pathology, yet be cognitively and functionally normal. Although the prevalence of Alzheimer’s disease in individuals over the age of 85 is approximately 45 percent, a proportion of remaining cognitively intact individuals display advanced AD-like neuropathology postmortem. Genetic factors that distinguish Alzheimer’s patients from cognitively normal, pathologically advanced individuals have remained elusive. Kramer and colleagues conducted an innovative genomewide association study (GWAS) to identify specific genetic variants associated with healthy brain aging with, or without, evidence of postmortem NFT formation in critical brain regions.
In their study, individuals were stratified into a low or high Braak category based on the extent of NFT burden. They identified three reelin (RELN) SNPs (i.e., rs4298437, rs6951875, and rs6943822) that were significantly associated with a high Braak category (odds ratios: 2.12-2.44). The rs6951875 SNP was in the RELN promoter region, while the other two SNPs were located in the 5’ region of the gene. Interestingly, additional reelin SNPs around the promoter region have been identified in a study of female AD patients (Seripa et al., 2008). Reelin immunostaining revealed an upregulation of reelin expression by pyramidal neurons in individuals carrying the RELN risk SNPs and belonging to the high Braak category, suggesting that reelin might be upregulated as a compensatory mechanism. These findings reveal that individuals carrying variants of the RELN gene that increase reelin expression may be protected from cognitive dysfunction, despite accumulation of NFTs and neuritic plaques.
The importance of RELN SNPs associated with AD is emboldened by numerous studies demonstrating that impairments in reelin signaling are intimately associated with the molecular processes underlying both the development and progression of AD pathology. Specifically, several groups have found that reelin negatively regulates tau phosphorylation through promoting the inactivation of GSK-3β (Hiesberger et al., 1999; Ohkubo et al., 2003; Trommsdorff et al., 1999). Work by Bill Rebeck’s group has also demonstrated that reelin directly promotes the non-amyloidogenic processing of APP. Indeed, reelin haploinsufficiency has been found to aggravate amyloid pathology, inflammation, and formation of neurofibrillary tangles in mice harboring the Swedish and Arctic APP mutations (Kocherhans et al., 2010). These studies strongly support a role for reelin as an upstream regulator of both tau and APP.
The reelin pathway may be particularly vulnerable to disruption by ApoE4, the major genetic risk factor for sporadic Alzheimer’s disease, as well as β amyloid. Recently, Joachim Herz’s group has found that reelin is important for protecting hippocampal neurons from β amyloid-induced suppression of long-term potentiation. Moreover, they have shown that ApoE4 selectively prevents reelin’s ability to mitigate the effects of β amyloid by sequestering the reelin receptor, ApoER2. A recent study (Botella-Lopez et al., 2010) has also found that β amyloid itself can directly affect the expression and glycosylation of reelin. An elevation in reelin expression (as is seen in high Braak patients carrying the identified RELN SNPs) may allow neurons to: 1) overcome impairments of normal reelin signaling, or 2) promote a gain-of-function of the reelin pathway that can counteract the effects of AD pathology on synaptic function. This is consistent with reports of reelin activating signal transduction pathways involved in learning and memory and enhancing synaptic plasticity, and our recent studies demonstrating that acutely increasing reelin in wild-type mice significantly enhances cognitive function (Rogers and Weeber, 2008).
The study by Kramer et al. provides important genetic evidence that the reelin pathway may play an active role in staving off the effects of age-related accumulation of toxic tau and β amyloid. Moreover, this genetic identification provides a novel molecular target to counter the pathologic effects of toxic amyloid and tau species.
Seripa D, Matera MG, Franceschi M, Daniele A, Bizzarro A, Rinaldi M, Panza F, Fazio VM, Gravina C, D'Onofrio G, Solfrizzi V, Masullo C, Pilotto A.
The RELN locus in Alzheimer's disease.
J Alzheimers Dis. 2008 Jul;14(3):335-44.
Hiesberger T, Trommsdorff M, Howell BW, Goffinet A, Mumby MC, Cooper JA, Herz J.
Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation.
Neuron. 1999 Oct;24(2):481-9.
Ohkubo N, Lee YD, Morishima A, Terashima T, Kikkawa S, Tohyama M, Sakanaka M, Tanaka J, Maeda N, Vitek MP, Mitsuda N.
Apolipoprotein E and Reelin ligands modulate tau phosphorylation through an apolipoprotein E receptor/disabled-1/glycogen synthase kinase-3beta cascade.
FASEB J. 2003 Feb;17(2):295-7.
Trommsdorff M, Gotthardt M, Hiesberger T, Shelton J, Stockinger W, Nimpf J, Hammer RE, Richardson JA, Herz J.
Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2.
Cell. 1999 Jun 11;97(6):689-701.
Kocherhans S, Madhusudan A, Doehner J, Breu KS, Nitsch RM, Fritschy JM, Knuesel I.
Reduced Reelin expression accelerates amyloid-beta plaque formation and tau pathology in transgenic Alzheimer's disease mice.
J Neurosci. 2010 Jul 7;30(27):9228-40.
Botella-López A, Cuchillo-Ibáñez I, Cotrufo T, Mok SS, Li QX, Barquero MS, Dierssen M, Soriano E, Sáez-Valero J.
Beta-amyloid controls altered Reelin expression and processing in Alzheimer's disease.
Neurobiol Dis. 2010 Mar;37(3):682-91.
Rogers JT, Weeber EJ.
Reelin and apoE actions on signal transduction, synaptic function and memory formation.
Neuron Glia Biol. 2008 Aug;4(3):259-70.