Alzheimer's disease and epilepsy: insight from animal models

Abstract

Alzheimer's disease (AD) and epilepsy are separated in the medical community, but seizures occur in some patients with AD, and AD is a risk factor for epilepsy. Furthermore, memory impairment is common in patients with epilepsy. The relationship between AD and epilepsy remains an important question because ideas for therapeutic approaches could be shared between AD and epilepsy research laboratories if AD and epilepsy were related. Here we focus on one of the many types of epilepsy, temporal lobe epilepsy (TLE), because patients with TLE often exhibit memory impairment, depression and other comorbidities that occur in AD. Moreover, the seizures that occur in patients with AD may be nonconvulsive, which occur in patients with TLE. Here we first compare neuropathology in TLE and AD with an emphasis on the hippocampus, which is central to both AD and TLE research. Then we compare animal models of AD pathology with animal models of TLE. Although many aspects of the comparisons are still controversial, there is one conclusion that we suggest is clear: some animal models of TLE could be used to help address questions in AD research, and some animal models of AD pathology are bona fide animal models of epilepsy.

Figures

Figure 1. A comparison of common perspectives of the pathophysiology in temporal lobe epilepsy and Alzheimer’s disease

(A) Some of the major stages in the sequence of progressive pathophysiology is shown for TLE where there is an early-life precipitating insult, and (B) AD, where Aβ accumulates gradually and diagnosis typically occurs after 50 years of age. The sequential stages are similar in several ways, including a stage where toxicity and plasticity is likely to be important in both diseases, and increased excitability is potentially a common theme. One major difference is the timeline, because the toxicity and plasticity is likely to occur much earlier in life in TLE, which has implications because of the increased plasticity of the young brain. Another major difference is the sudden and severe nature of the initial stage in TLE, at least for acquired TLE, compared with common conceptions of AD etiology. The sudden, severe and earlier timeline for TLE could be what contributes to the different outcomes in AD and TLE. Aβ: Amyloid β; AD: Alzheimer’s disease; APP: Amyloid precursor protein; TLE: Temporal lobe epilepsy.

Figure 2. The normal dentate gyrus and changes in animal models of temporal lobe epilepsy and Alzheimer’s disease

(A) The normal dentate gyrus of the rodent and primate is shown. There are three layers, the molecular layer, granule cell layer (containing the major cell type, the granule cells) and hilus. All layers contain various types of GABAergic interneurons, and only two are shown: the PV-immunoreactive basket cell (blue), and the SS/NPY hilar cells (HIPP cells; red) that innervate the outer two-thirds of the molecular layer, the location of the major cortical input from the layer II neurons of the entorhinal cortex. Besides granule cells, there is one other type of glutamatergic cell in the hilus called the mossy cell, which terminates primarily in the inner third of the molecular layer. Axonal projections are usually laminar specific, and shown to the right. (B) In rodent models of TLE where SE is used to induce epilepsy in adulthood, there are many differences in the way the SE is induced, but some common changes in circuitry occur, and these are illustrated schematically. These changes include loss of hilar neurons, including HIPP and mossy cells. There is sprouting of mossy fibers into the inner molecular layer, where granule cells appear to be targeted primarily, although some interneurons are also innervated. Another common finding is sprouting of GABAergic interneurons into the molecular layer. (C) In amyloid precursor protein (APP) or APP-PS1 mouse models of AD pathology, there are differences in APP (or PS1) mutations and promoters to drive expression, as well as background strain, but there are some of the common findings from studies of hAPP and APde9 mice, which are shown schematically. Remarkably, changes are similar to those in (B). Exceptions include relatively more preservation of hilar cells, and less mossy fiber sprouting. AD: Alzheimer’s disease; NPY: Neuropeptide Y; PV: Parvalbumin; SE: Status epilepticus; SS: Somatostatin; TLE: Temporal lobe epilepsy.

Figure 3. Immunoreactivity in the normal dentate gyrus and the dentate gyrus in epileptic rats using an antibody to the calcium-binding protein calbindin D28K

(A) Immunocytochemistry of the normal adult rat dentate gyrus using an antibody to the calcium-binding protein calbindin D28K shows that granule cell bodies in the GCL are stained, including granule cell dendrites in the Mol, granule cell axons (mossy fibers) in the hilus and mossy fibers in area CA3. Calibration = 100 μm. (B & C) In status epilepticus (SE) models, there are several changes in calbindin immunoreactivity. One that we have found is novel staining of hilar neurons or neurons at the border of the hilus and granule cell layer that have very large somata and thick but aspiny dendrites compared with granule cells (arrows). These neurons may reflect hypertrophied interneurons in SE models, which has recently been reported for somatostatin-immunoreactive hilar cells [107]. Calibration in (C) = 100 μm. (D) Calbindin immunocytochemistry in the granule cell layer of rats that are epileptic after SE induction show weak expression in the inner and outer third of the layer, and patches of the layer where all granule cells exhibit weak expression. The arrows points to the top and bottom of the granule cell layer which is blue. The patchy labeling of granule cells was shown in hAPP, APde9 and another mouse model of Alzheimer’s disease pathology [6,7,101] and in human specimens from Alzheimer’s disease and temporal lobe epilepsy [98]. Calibration = 200 μm. (E) Higher magnification of the area of (D) at the arrows. Arrows indicate the top of the granule cell layer and the base. Calibration in (D) = 100 μm. Reproduced with permission from [114]. GCL: Granule cell layer; Mol: Molecular layer; SGZ: Subgranular zone.

Figure 4. Inverse relationship between c-fos and calbindin immunoreactivity in the epileptic dentate gyrus of rats

(A & B) The dentate gyrus of a rat that had status epilepticus and developed chronic seizures is shown, stained with an antibody to calbindin and counterstained with cresyl violet. Note that the GCL (blue) is stained for calbindin only in the center of the layer, and there are areas where there is an absence of calbindin in the cell layer (arrows). Arrowheads point to hypertrophied aspiny cells, similar to those in Figure 3. (C & D) An adjacent section to the one in (A) is shown, stained with an antibody to c-fos. Note that where c-fos is expressed in the GCL there is reduced expression of calbindin (arrows) and where c-fos expression is weak (arrowheads), there is strong expression of calbindin. Calibration shown in (A) is 100 μm for (A) and (C). Calibration is 50 μm for (B) and (D). GCL: Granule cell layer; Mol: Molecular layer.

Figure 5. Mossy fiber sprouting in epileptic rodents is not necessarily homogeneous

(A & B) Mossy fibers of an epileptic rat that experienced pilocarpine-induced status epilepticus (SE) are stained with an antibody to neuropeptide Y (NPY). (A) In the septal pole of the hippocampus, a coronal section illustrates NPY staining primarily in the locations where mossy fibers normally terminate, the hilus of the dentate gyrus and stratum lucidum (arrows) of area CA3. (B) In the temporal pole of the same hemisphere, cut in the horizontal plane, there is striking mossy fiber sprouting in the inner Mol (arrows) that appears to be absent in (A). (C) NPY immunoreactivity in a control rat is primarily exhibited by hilar neurons (axons) and their fibers. (D) In an epileptic rodent, where granule cell axons exhibit NPY immunoreactivity, sprouting is typically inferred from the NPY immunoreactivity in the inner Mol (arrows). A section is shown from a rat that experienced pilocarpine-induced SE. (E) In other epileptic rodents that were treated the same way as the animal in (D), and evaluated at similar times after SE, mossy fiber sprouting is more robust. NPY immunoreactivity is greater and the plexus in the inner Mol (arrows) appears to be larger. Therefore, mossy fiber sprouting may not be homogeneous in the septotemporal axis of the same animal or across animals. Similar observations have been reported in other SE models and in surgical specimens from patients with intractable TLE [78]. (A & B) Modified with permission from [82]. GCL: Granule cell layer; IML: Inner molecular layer; Mol: Molecular layer.

Figure 6. Schematic representation of the progressive pathophysiology

A schematic is shown that is based on a comparison of the dentate gyrus of animals that experienced SE and developed a temporal lobe epilepsy-like condition (top; SE model), or hAPP/APde9 mice, which have been shown to exhibit recurrent seizures (bottom, AD model). We suggest that there are two major differences: the sudden time course of the early event in the SE model, and increased neuronal loss in the hilus and increased mossy fiber sprouting in the SE model. If hilar cell loss increases dentate gyrus excitability and mossy fiber sprouting increases recurrent excitation, as has been suggested [54,56,57,79], these differences could account for the increased propensity for seizures in the SE model. AD: Alzheimer’s disease; SE: Status epilepticus.