Lane-Donovan C, Philips GT, Wasser CR, Durakoglugil MS, Masiulis I, Upadhaya A, Pohlkamp T, Coskun C, Kotti T, Steller L, Hammer RE, Frotscher M, Bock HH, Herz J. Reelin protects against amyloid β toxicity in vivo. Sci Signal. 2015 Jul 7;8(384):ra67. PubMed.

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  1. Joachim Herz and his lab have accomplished a milestone in research on the biology of reelin, a protein that has complex biochemistry and genetic contributions to brain development, as well as synaptic plasticity in the adult. Because it is so critical for the correct patterning of cortical layers during neural development, reelin’s roles at adult synapses have not been amenable to investigation via germline-knockout animals. Lane-Donovan et al. now report the results of a conditional knockout (cKO) that ablates reelin only in the forebrain and only after the cortical layers have been established. Their results are very important, and not without a few surprises.

    Reelin is perhaps most relevant to Alzheimer’s disease because its most important effects are mediated by a pair of lipoprotein receptors that are also binding sites for ApoE.  Although several members of the LDL-receptor family have biological effects that indicate roles other than lipid transport, apoER2 and VLDLR have very acute, well-characterized impacts on signal transduction via an intracellular accessory protein called Dab1. Agonism of apoER2 or VLDLR, apparently via the formation of dimers or other multimers induced by multimeric ligands, leads to tyrosine phosphorylation of Dab1, and this propagates signals to important post-synaptic proteins. A key downstream event is accentuation of NMDA receptor responses, thus the reelin→apoER2→Dab1 pathway can make important contributions to long-term potentiation (LTP) and other types of synaptic plasticity dependent on NMDA receptors. One might imagine that interruptions in this pathway could therefore underlie the memory deficits apparent in dementia.

    Prior studies have indicated that ApoE opposes the actions of reelin in some respects. Dr. Herz has contributed to that body of work with demonstrations that the antagonism involves ApoE binding to apoER2 and evoking ligand-stimulated receptor internalization, temporarily taking the apoER2 “out of commission” regarding reelin signaling. ApoE4 was reported to hold the receptor inside the cell longer than did ApoE3; the latter allowed quicker recycling of the receptor to the cell surface. Thus, one potential mechanism by which inheritance of an ε4 allele of ApoE fosters Alzheimer’s disease is by inhibiting reelin’s ability to enhance LTP and, thus, memory. Because Aβ has been demonstrated to bind other LDL-receptor family members, it is also conceivable that Aβ could antagonize reelin actions.

    Together, these prior studies on reelin—conducted either in reelin heterozygotes or with anti-reelin antibodies—made some of the results obtained here by Lane-Donovan et al. surprising. The reelin-cKO mice they generated reportedly had no deficits in memory and actually showed enhancements in their capacity for LTP. Given the diminutions of LTP when reelin has been lowered or inhibited in other paradigms, this is counterintuitive. Perhaps the complete (vis à vis the heterozygote paradigm) and subchronic (vis à vis acute application of an antibody) removal of reelin results in overcompensation by some reactive or redundant mechanism. 

    Another of the surprises among the reelin cKO results is that this manipulation did not lead to dispersion of the dentate granule cells of the hippocampal formation. Adult neurogenesis produces continuous renewal of dentate granule cells from the subgranular zone. Healthy hippocampal circuitry requires proper migration of the newborn cells to the narrow granule cell layer, and prior studies have found that disruption of any member of the reelin→apoER2/VLDLR→Dab1 pathway leads to inappropriate migration. The aberrant migrations cause a disruption of normal circuitry and produce epileptiform activity. Indeed, temporal-lobe seizures—either experimentally induced or those that naturally occur in human patients—are correlated with diminished levels of reelin. The emerging recognition of subtle epileptiform activity in AD thus makes reelin’s role in these events another point of intrigue for AD researchers. However, Lane-Donovan et al. report that the removal of reelin in their mice for a month had no adverse effects on dentate organization. The authors discuss this in relation to one other experimental paradigm that implicated reelin in granule cell dispersion, and they suggest that their results may indicate a role for other reelin receptors that exert a “dominant-negative interference” when only apoER2/VLDLR-mediated events are lost. But this seems a bit of a challenge to Occam’s Razor. It seems more likely that whatever compensatory response was responsible for the reversal of the expected LTP drop also created compensation regarding granule cell migration.

    The primary take-home message Lane-Donovan et al. would leave us with is that loss of reelin renders enhanced vulnerability to the Aβ-dependent behavioral deficits seen in APPsw (Tg2576) mice. This line typically performs well in the Morris water maze until 9 to 10 months of age, but in combination with cKO of reelin, deficits were apparent in mice at just 7 months of age; this, despite reelin cKO having no detected effects on accumulation of soluble or insoluble Aβ. These results are subject to a considerable caveat, however: As Lane-Donovan et al. remind us, Dab1 can be modulated by several other membrane proteins, most notably for readers here, APP itself. Evidence suggests that APP can act as a decoy to remove Dab1 from the transduction of reelin signaling. The APP transgene is expressed at five- to 10-fold that of normal endogenous levels in Tg2576 mice, and it may therefore exert the sort of “dominant-negative interference” Lane-Donovan et al. invoke for other phenomena. Without a reversal by Aβ immunization or the like, it is not possible to conclude definitively that the memory deficits seen here reflect a cooperative effect of reelin loss and Aβ production. 

    Nevertheless, it certainly is possible that an Aβ-dependent effect is at work here. It might be worth considering that the Aβ present in Tg2576 mice differs from that present when reelin is simply removed from the cKO mice. The authors point out that such a removal is less prone to artifacts than the complementary overexpression studies, where reelin may be expressed at inappropriate sites and certainly at supraphysiological levels. However, the one thing that such a simple KO (even the conditional sort) cannot tell us is how reelin might functionally interact with human Aβ. The sequence of the mouse peptide is famously resistant to aggregation and may not be capable of exerting pathogenic actions when relieved of a reelin-mediated antagonism. If reelin has no dramatically important roles in adults other than Aβ antagonism—which Lane-Donovan et al. would seem to suggest—knocking it down or out in mice will not be particularly informative unless the Aβ is humanized. So, as with so many other fascinating questions in the AD field, the best data may yet come from studies performed in the context of an APP knock-in mouse, such as those created by Cephalon researchers, by Christoph Köhler, or by Takaomi Saido.

    View all comments by Steve Barger

  2. In an elegant set of experiments, Herz and colleagues have continued to shed light on the role of reelin in synaptic function and provide further evidence for the protective nature of reelin against amyloid-associated synaptic plasticity and memory dysfunction using a novel mouse model; the inducible reelin knockout (reelin cKO) mouse. The reelin cKO model reveals that adult knockdown of reelin expression results in no discernable differences in learning and memory, but in contrast causes enhanced hippocampal late-phase LTP. These mice show an increase in the expression of the intracellular adaptor protein disabled-1, without significant alterations in other downstream effectors, glutamate receptors, or tau phosphorylation. They also show normal cerebellar, hippocampal, and cortical lamination and development and no differences in dendritic spine morphology. These findings set the stage for a cross of the reelin cKO with the Tg2576 (APP overexpressing) AD mouse model. Interestingly, these crosses did not show increased Aβ pathology; however, they were more susceptible to the detrimental effects of Aβ on spatial learning and memory and the enhanced late-phase LTP phenotype was lost. These results suggest that endogenous reelin can be protective against memory loss associated with AD pathology and raises the interesting possibility that reduced reelin expression in the early stages of AD may underlie the initial symptoms associated with mild cognitive impairment. Furthermore, in the normal aged brain, reduced reelin expression may not be as detrimental to cognitive ability as what was predicted from earlier mouse models.

    View all comments by Edwin J. Weeber

  3. Loss of reelin in embryonic development leads to profound consequences in brain development (such as disrupted cortical layering), making it hard to delineate what impact reelin deficiency has in the adult brain. Therefore, the reelin conditional knockout (cKO) generated by the authors is an important tool for researchers who want to study reelin’s impact on adult function.

    The authors demonstrate that adult reelin cKO mice have normal brain structure, normal cognitive function, and a moderate enhancement of long-term potentiation (LTP) compared to controls. After characterizing this animal model, the authors crossed the cKO mice with a Tg2576 AD model. Although loss of reelin did not accelerate Ab plaque load at early stages in the Tg2576 background, it accelerated cognitive deficits. This study complements a study that reported that reelin supplementation promotes cognitive and synaptic function in wild-type mice (Rogers et al., 2011). Taken together, these findings strengthen the case for reelin being a viable therapeutic target to address the cognitive impairments observed in AD. It would be interesting to address whether loss of reelin in human AD patients correlates with cognitive deficits independently of plaque load.

    References:

    Rogers JT, Rusiana I, Trotter J, Zhao L, Donaldson E, Pak DT, Babus LW, Peters M, Banko JL, Chavis P, Rebeck GW, Hoe HS, Weeber EJ. Reelin supplementation enhances cognitive ability, synaptic plasticity, and dendritic spine density. Learn Mem. 2011 Sep;18(9):558-64. Print 2011 Sep PubMed.

    View all comments by Hyang-Sook Hoe

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