Leonard AS, McNamara JO.
Does epileptiform activity contribute to cognitive impairment in Alzheimer's disease?.
Neuron. 2007 Sep 6;55(5):677-8.
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Comment by Jorge J. Palop and Lennart Mucke
We completely agree with Dr. Ashford in that the specific connection between Aβ and tau revealed by this and our previous study (Roberson et al., 2007) deserves to be explored further. However, we believe that the potential role of Aβ-induced aberrant overexcitation in the pathogenesis of AD may have been underestimated.
As highlighted by our study, much of such activity is non-convulsive and, thus, could easily escape detection by standard clinical exams. Our study also revealed a striking compensatory remodeling and activation of inhibitory circuits, which could account for the fact that obvious convulsive seizures are not frequent in this condition.
However, convulsive seizures are probably more frequent in AD than many clinicians realize. As discussed in our paper, AD patients clearly have a higher incidence of seizures than reference populations (Amatniek et al., 2006; Hauser et al., 1986; Hesdorffer et al., 1996; Lozsadi and Larner, 2006; Mendez and Lim, 2003).
Interestingly, the risk of epileptic activity is particularly high in AD patients with early-onset dementia and during the earlier stages of the disease, reaching an 87-fold increase in seizure incidence compared with an age-matched reference population (Amatniek et al., 2006; Mendez et al., 1994). Thus, aberrant neuronal overexcitation may play an important role not only in hAPP mouse models, but also in the pathogenesis of dementia in sporadic AD.
Indeed, epileptiform activity has been associated with transient episodes of amnestic wandering and disorientation in AD (Rabinowicz et al., 2000). It is interesting in this regard that the relationship between seizures and AD is even tighter in autosomal-dominant early-onset FAD. Pedigrees with epilepsy have been identified in FAD linked to mutations in presenilin-1, presenilin-2, and APP (Edwards-Lee et al., 2005; Marcon et al., 2004; Snider et al., 2005). More than 30 different mutations in presenilin-1 are associated with seizures (Larner and Doran, 2006). Our results suggest that the increased epileptic activity in sporadic and autosomal-dominant AD may be caused by Aβ-induced increases in network excitability. Future studies will need to test the hypothesis that this alteration contributes critically to the pathogenesis of AD, objectively and without preconceived notions about outcomes.
This is a significant advance in understanding how networks are affected in AD. The recent report by Kim et al. that the α-, β-, and γ-secretases process, and regulate expression and function of, the β2 subunit of voltage-sensitive sodium channels suggests that widespread changes in neuronal excitability in AD may have a more fundamental explanation than effects on transmitter receptors.
Palop et al. clearly demonstrate neural network dysfunction in hAPPFAD-mice. Our recent study also supports neural network dysfunction in AD patients, as a consequence of elevated BACE1 activity rather than a direct effect of increased Aβ levels. We found that BACE1 regulates voltage-gated sodium channel levels and surface expression through processing of its β2 subunit (Kim et al., 2007). In particular, increased BACE1 activity reduces surface Nav1.1 sodium channel expression and sodium current by 50 percent in hippocampal neurons from BACE1-transgenic mice as compared to wild-type controls. Haploinsufficiency of Nav1.1 induces epileptic seizures in mouse and human by preferentially decreasing sodium currents in GABAergic inhibitory neurons (Yu et al., 2006; for humans, see a review by Meisler and Kearney, 2005). For this reason, we predicted that elevated BACE1 activity in AD would alter sodium channel metabolism, leading to neural network dysfunctions such as seizures (Kim et al., 2007).
It will be interesting to examine the specific contribution of the two pathways to neural network dysfunction in AD patients: one via elevated BACE1 activity leading to voltage-gated sodium channel dysfunction, the other via elevated Aβ with unclear molecular mechanism. These two pathways may be separate, both contributing to network dysfunction in AD patients. The former may affect membrane excitability/neuronal activity in the axons, soma, and dendrites of neuronal cells while the latter may directly affect synapses. However, they can also interact with each other. Zhao et al. recently reported that amyloid plaques induce BACE1 in surrounding neurons in mice and AD brains (Zhao et al., 2007). Therefore, elevated BACE1 by Aβ plaques could also contribute to network dysfunction and non-convulsive seizure activities by altering sodium channel metabolism. Elevated BACE1 activity increases Aβ generation in AD patients as well as sodium channel dysfunction, both of which can synergistically contribute to the network dysfunction. The interaction of these two pathways will be an interesting subject to explore in relation to AD pathogenesis.