Epilepsy and cognitive impairments in Alzheimer disease

Abstract

Alzheimer disease (AD) is associated with cognitive decline and increased incidence of seizures. Seizure activity in AD has been widely interpreted as a secondary process resulting from advanced stages of neurodegeneration, perhaps in combination with other age-related factors. However, recent findings in animal models of AD have challenged this notion, raising the possibility that aberrant excitatory neuronal activity represents a primary upstream mechanism that may contribute to cognitive deficits in these models. The following observations suggest that such activity may play a similar role in humans with AD: (1) patients with sporadic AD have an increased incidence of seizures that appears to be independent of disease stage and highest in cases with early onset; (2) seizures are part of the natural history of many pedigrees with autosomal dominant early-onset AD, including those with mutations in presenilin-1, presenilin-2, or the amyloid precursor protein, or with duplications of wild-type amyloid precursor protein; (3) inheritance of the major known genetic risk factor for AD, apolipoprotein E4, is associated with subclinical epileptiform activity in carriers without dementia; and (4) some cases of episodic amnestic wandering and disorientation in AD are associated with epileptiform activity and can be prevented with antiepileptic drugs. Here we review recent experimental data demonstrating that high levels of beta-amyloid in the brain can cause epileptiform activity and cognitive deficits in transgenic mouse models of AD. We conclude that beta-amyloid peptides may contribute to cognitive decline in AD by eliciting similar aberrant neuronal activity in humans and discuss potential clinical and therapeutic implications of this hypothesis.

Figures

Figure 1. βAmyloid (Aβ) can affect neuronal activity at multiple levels of complexity

High levels of Aβ depress excitatory synaptic transmission and impair synaptic plasticity at the level of specific synapses (A) but elicit epileptiform activity and seizures at the network level (B). Whether there is a causal relationship between these Aβ effects is unknown. F indicates frontal; fEPSP, field excitatory postsynaptic potentials; H, hippocampal; hAPPJ20, human amyloid precursor protein transgenic mice; L, left; NTG, nontransgenic mice; O, posterior-parietal; P, parietal; R, right; T, temporal; and TBS, {theta}-burst stimulation. Adapted from Neuron and Nature.

Figure 2. Our latest view of the β-amyloid (Aβ) cascade hypothesis and resultant hippocampal remodeling

A, High levels of Aβ induce epileptiform activity, which triggers compensatory inhibitory responses to counteract overexcitation. Both aberrant excitatory neuronal activity and compensatory inhibitory responses may contribute to Alzheimer disease–related cognitive deficits. B, Aβ-dependent circuit remodeling in the dentate gyrus of human amyloid precursor protein transgenic mice (hAPPJ20). In contrast to nontransgenic mice (NTG), hAPPJ20 mice show increased sprouting of inhibitory axonal terminals in the molecular layer, enhanced synaptic inhibition, ectopic neuropeptide Y (NPY) expression in granule cells, and depletion of activity-dependent proteins such as calbindin, Arc, and Fos. These alterations likely reflect compensatory inhibitory responses to aberrant excitatory neuronal activity. CB indicates calbindin; GABA, {gamma}-aminobutyric acid; Glu, glutamate; PV, parvalbumin; and SOM, somatostatin. Adapted from Neuron.

Figure 3. Tau reduction prevents β-amyloid (Aβ) toxicity in vivo

Thioflavin-S staining (A) and anti-Aβ immunostaining (B) of hippocampal amyloid plaques in mice with human amyloid precursor protein transgenic mice (hAPPJ20) with 2 (tau+/+) or no (tau−/−) functional tau alleles revealed that tau reduction did not alter plaque loads in hAPP mice. However, tau reduction effectively prevented Aβ-induced depletion of calbindin (CB) (C) and increases in neuropeptide Y (NPY) (D) in the dentate gyrus as well as spatial memory deficits in the Morris water maze (E). The representative path tracings in (E) were obtained in a probe trial (platform removed) 24 hours after 3 days of hidden platform training. Tau reduction markedly increased focused search activity in the target quadrant (light gray) and over the platform location (dark gray), suggesting improved spatial memory retention. Adapted from Neuron and Science.