Andrews-Zwilling Y, Bien-Ly N, Xu Q, Li G, Bernardo A, Yoon SY, Zwilling D, Yan TX, Chen L, Huang Y. Apolipoprotein E4 causes age- and Tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice. J Neurosci. 2010 Oct 13;30(41):13707-17. PubMed.
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Comments
UT Southwestern
This paper by Huang and colleagues points toward an interesting role of GABAergic interneurons as potential intermediaries in the pathogenesis of Alzheimer disease. Although the mechanisms by which ApoE4 predisposes to AD are still under lively debate, this paper now adds new evidence that may help to synthesize some of the different molecular processes that have been proposed into a coherent model.
Our group has recently shown that ApoE4 selectively impairs ApoE receptor trafficking and signaling, as well as glutamate receptor trafficking and activation (see ARF related news story on Chen et al., 2010), resulting in greatly impaired synaptic response to the positive neuromodulator Reelin, and a concomitant increased susceptibility to synaptic suppression by β amyloid. ApoE receptor signaling by Reelin directly suppresses tau phosphorylation (see ARF related news story on Brich et al., 2003) and protects from age-dependent neuronal loss (Beffert et al., 2006).
The current paper provides further evidence that these mechanisms may be related. It is also consistent with a model in which neuronal network disruption (Palop and Mucke, 2010) is a key driver of Alzheimer’s pathogenesis, involving impaired ApoE receptor signaling (see ARF related news story on Durakoglugil et al., 2009) in the presence of ApoE4 (Chen et al., 2010).
References:
Chen Y, Durakoglugil MS, Xian X, Herz J. ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling. Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):12011-6. Epub 2010 Jun 14 PubMed.
Brich J, Shie FS, Howell BW, Li R, Tus K, Wakeland EK, Jin LW, Mumby M, Churchill G, Herz J, Cooper JA. Genetic modulation of tau phosphorylation in the mouse. J Neurosci. 2003 Jan 1;23(1):187-92. PubMed.
Beffert U, Nematollah Farsian F, Masiulis I, Hammer RE, Yoon SO, Giehl KM, Herz J. ApoE receptor 2 controls neuronal survival in the adult brain. Curr Biol. 2006 Dec 19;16(24):2446-52. PubMed.
Durakoglugil MS, Chen Y, White CL, Kavalali ET, Herz J. Reelin signaling antagonizes beta-amyloid at the synapse. Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15938-43. PubMed.
UTSW Medical Center
Yadong Huang and colleagues have previously shown that ApoE plays an important role in adult hippocampal neurogenesis, and the ApoE4 isoform impairs GABAergic input to newborn neurons (1). In this follow-up paper, they describe the functional significance of GABAergic impairment, as the extent of deficit in learning and memory correlates with the neurotoxic ApoE4 fragment. They also show that the loss of GABAergic interneurons depends on the presence of tau.
There are several interesting aspects to this work. One, since it shows that ApoE polymorphism plays a central role in the maintenance of GABAergic interneurons, it reinforces the idea that the ApoE genotype might be affecting the risk of AD, at least partially through effects on synaptic function (2,3). Two, it identifies new potential targets for AD therapeutic approaches, i.e., activation of GABAergic receptors. Three, they provide a functional connection between the neurotoxic effect of ApoE4 and tau phosphorylation.
This research supports some very interesting avenues for further study with some new questions. Does ApoE affect normal functions of tau? What role does amyloid-β play in this model? Is there a role for sex hormones in ApoE4 toxicity? Do GABAergic interneurons play a role in other neurological diseases? Would targeting the molecules identified in their model of synaptic dysfunction in AD be useful in preventing the progression of the disease? We now have to consider if we need to extend our old model of a “cholinergic” theory of AD to include a “GABAergic “model of pathogenesis.
References:
Li G, Bien-Ly N, Andrews-Zwilling Y, Xu Q, Bernardo A, Ring K, Halabisky B, Deng C, Mahley RW, Huang Y. GABAergic interneuron dysfunction impairs hippocampal neurogenesis in adult apolipoprotein E4 knockin mice. Cell Stem Cell. 2009 Dec 4;5(6):634-45. PubMed.
Durakoglugil MS, Chen Y, White CL, Kavalali ET, Herz J. Reelin signaling antagonizes beta-amyloid at the synapse. Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15938-43. PubMed.
Chen Y, Durakoglugil MS, Xian X, Herz J. ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling. Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):12011-6. Epub 2010 Jun 14 PubMed.
Gladstone Institutes/UCSF
By demonstrating a selective vulnerability of hilar interneurons to intracellularly generated neurotoxic ApoE4 fragments, Andrews-Zwilling et al. identified an interesting new mechanism through which ApoE4 could contribute to neural network dysfunction in AD. While this mechanism is most likely independent of Aβ, it could synergize with Aβ-induced alterations in GABAergic functions. Human amyloid precursor protein (hAPP) transgenic mice show a prominent sprouting of GABA/neuropeptide Y-positive fibers in the outer molecular layer of the dentate gyrus, which likely emanates from hilar interneurons and represents efforts to close the “hippocampal gate” and protect the hippocampus against aberrant excitatory inputs from the cortex (Palop et al., 2007). Impairment of these interneurons by ApoE4 would be expected to disable this defense mechanism, exacerbating bouts of overexcitation and promoting excitotoxicity. Notably, Andrews-Zwilling et al. also identified tau reduction as an effective strategy to prevent the ApoE4-induced degeneration of hilar interneurons. While it is possible that tau ablation eliminated a toxic tau mediator generated by some ApoE4 activity, it is also possible that tau reduction was beneficial because of its antiepileptic effect, which increases resistance to Aβ-induced cognitive impairments and chemically induced seizures (Roberson et al., 2007; Ittner et al., 2010). These possibilities are not mutually exclusive, have important therapeutic implications, and deserve to be explored further in future studies.
References:
Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, Yoo J, Ho KO, Yu GQ, Kreitzer A, Finkbeiner S, Noebels JL, Mucke L. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron. 2007 Sep 6;55(5):697-711. PubMed.
Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu GQ, Mucke L. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science. 2007 May 4;316(5825):750-4. PubMed.
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. Epub 2010 Jul 22 PubMed.
University of South Florida
The paper by Yadong Huang and colleagues describes the use of the well-established apolipoprotein E4 and E3 knock-in (KI) mice originally developed by Patrick Sullivan. The current research describes a significant decrease in GABAergic interneurons in the hilus of the hippocampus in 16-month-old mice compared to ApoE3 KI mice. This decrease is associated with an appreciable decrease in GABAergic synaptic function. Interestingly, this decrease is not seen in the neighboring CA1 region, suggesting a region-specific defect associated with ApoE4 expression. Using the Morris hidden platform water maze to test spatial learning and memory, the researchers saw no changes in wild-type, ApoE3 KI, or ApoE4 KI mice at 12 months of age. However, 16-month-old, or older, ApoE4 KI mice show a significant increase in platform-finding latencies during training and decreased target quadrant time five days following the last training session. The observed deficit in spatial learning and memory nicely correlates to hilar GABAergic impairment. These findings are further strengthened by the rescue of spatial learning and memory in 16-month-old ApoE4 KI mice with injection of the GABAA receptor potentiator pentobarbital.
A possible mechanism for ApoE4 expression-dependent GABAergic impairment is the production of toxic ApoE cleavage fragments, specifically attributed to the E4 isoform, leading to increases in phosphorylated tau. This possibility was tested using a transgenic mouse that expressed low levels of ApoE4 toxic fragment (ApoE4 Δ272-299). These mice show significant GABAergic interneuron cell loss and impaired spatial learning and memory, but when crossed with tau-deficient mice (tau -/-), there was significantly less GABAergic interneuron loss and the spatial memory defect was rescued as well. Furthermore, the learning and memory rescue using the tau -/- cross was reversed with a sub-threshold dose of the GABA receptor antagonist picrotoxin.
These studies suggest that impairment of learning and memory in the ApoE4-expressing mice is due to the toxic cleavage of ApoE4 itself. This leads to increased tau phosphorylation and reduced GABAergic interneurons, specifically those in the hilar region of the hippocampus. Moreover, the authors find that mice with <2,500 hilar interneurons have greater spatial learning and memory defects. These results are the first to suggest a mechanism for the behavioral differences in ApoE4- versus ApoE3-expressing KI mice, but also point to a specific region of the hippocampus that appears to be particularly susceptible to ApoE4 toxic fragments. The learning and memory defects may be a result of GABAergic interneuron synaptic loss, altered tau phosphorylation, or perhaps reduced interneuron reelin production. While the presented evidence is focused on the hilar region of the hippocampus, it is unclear why this region appears to be so sensitive. This may be indicative of an area of “first defense” against excitatory input into the tri-synaptic pathway of the hippocampus, but most likely there is impairment in other regions of the hippocampus without significant interneuron loss. This may help to explain the ApoE isoform expression-dependent differences in CA1 LTP induction as well. Regardless, these studies reveal a possible link among ApoE4 expression, memory impairment, and Alzheimer disease pathogenesis through alterations in tau and interneuron loss that is independent of β amyloid. Furthermore, it indicates that ApoE4 expression in and of itself may underlie memory loss in early-stage AD, and cleavage prevention could represent a potential therapeutic target.
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