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   Read more

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).

View all comments by Joachim Herz

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....  Read more

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:
1. 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. Abstract

2. 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. Abstract

3. 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. Abstract

View all comments by Murat Durakoglugil

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...  Read more

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.

View all comments by Lennart Mucke

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...  Read more

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.

View all comments by Edwin J. Weeber

Loss of synaptic inhibition is a well-established cause of seizures, and this new study supports previous work from this laboratory showing that transplanted interneuronal precursors can become active participants in a hyperexcitable circuit and silence seizures in a genetic mouse model of epilepsy. Here, the model employed was a healthy mouse injected with a chemical convulsant, pilocarpine, that induces a hippocampal seizure focus sharing similarities with human temporal lobe epilepsy, but different in that brain development was otherwise normal and the circuit properties, while prone to generating seizures, are vastly different. In this model, grafted precursors not only reduced seizures, but also even improved performance deficits on behavioral tests relevant to hippocampal function. The authors conclude the approach holds promise not only for intractable epilepsies, but also perhaps other disorders that include altered hippocampal function such as Alzheimer’s disease and autism.

The groundbreaking aspects of this research are clear and mark a giant step toward a future...  Read more

Loss of synaptic inhibition is a well-established cause of seizures, and this new study supports previous work from this laboratory showing that transplanted interneuronal precursors can become active participants in a hyperexcitable circuit and silence seizures in a genetic mouse model of epilepsy. Here, the model employed was a healthy mouse injected with a chemical convulsant, pilocarpine, that induces a hippocampal seizure focus sharing similarities with human temporal lobe epilepsy, but different in that brain development was otherwise normal and the circuit properties, while prone to generating seizures, are vastly different. In this model, grafted precursors not only reduced seizures, but also even improved performance deficits on behavioral tests relevant to hippocampal function. The authors conclude the approach holds promise not only for intractable epilepsies, but also perhaps other disorders that include altered hippocampal function such as Alzheimer’s disease and autism.

The groundbreaking aspects of this research are clear and mark a giant step toward a future where severe focal epilepsies might be managed by cellular repair of damaged brain tissue rather than surgical removal. However, the findings are so counterintuitive that the authors should almost be chastened for their modest restraint in the Discussion. During brain development, over 21 different specific types of interneurons are painstakingly wired to precisely modulate the timing and firing patterns of hippocampal neurons. Who would imagine, given their diverse, highly individualized “personalities,” that simple addition of inexperienced newcomers could re-stabilize a normal pattern of synaptic inhibition in a network that is so severely compromised? And that their fates and excitability, which shift dramatically in immature brain, would retain properties similar to those they are intended to replace? The epileptic circuit in this model has been well studied and displays remarkable evidence of molecular and structural remodeling. Apparently, these fresh cells receive sufficient anatomic and biological guidance from the hyperactive network to quell the seizures, and the precise positioning of GABAergic synapses and the ratio of peptide co-transmitters they release are not as important as we may have thought.

While fresh interneurons may prove to be a panacea for lowering seizure thresholds, they may be less so for other measures of hippocampal function. An alternative view is that, whereas some behavioral measurements improved, this might be due to the reduction in seizures in these networks rather than the establishment of repaired hippocampal information processing. For the Alzheimer’s disease brain, the results are therefore less clear. So far, essentially all experimental mouse models of AD show seizure phenotypes, and recent data suggest that elimination of the seizures, for example, by tau removal, is accompanied by improved cognitive function. Some component of the cognitive loss may therefore actually represent an "epileptic pseudo-dementia" that may be reversible by silencing seizure activity. In the absence of seizures, it is unclear how well cellular grafting of interneurons, or any other type of cellular progenitor, will repair hippocampal function. Furthermore, the primarily neurodegenerative nature of the AD microenvironment suggests that even if temporarily effective, survival of the transplanted cells would be inexorably compromised, as they are in temporal lobe epilepsy, where cell death and hippocampal atrophy are also the hallmarks of the disease process. But if all we needed was a steady supply of fresh neurons, could an indwelling precursor brain cell reservoir supply them?

View all comments by Jeffrey L. Noebels