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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.
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Stanford / VA Aging Clinical Research Center
This is an interesting paper coming from an excellent research group. I agree that neural networks and synaptic plasticity are at the center of Alzheimer disease (Ashford and Teter, 2002), but in interpreting the relevance of this study to AD, we should also keep several issues in mind. This work is in mice, which only model a small part of the Alzheimer pathology. Further, β amyloid is associated with vulnerability to Alzheimer disease, but the dementia is due to a tauopathy, so any potential connection between Aβ and tau effects hinted at in the bigenic mice needs to be more specifically explored.
In my clinical experience, the epileptic issues in AD are less than described here. Alzheimer patients rarely have seizures, and the ones we reported in the literature were related to anti-cholinesterase drugs (Piecoro et al., 1998).
The concept of looking at a whole neural network and seeing how it responds to amyloid stress is very interesting. At the same time, the development of the plaques and tangles seems to be more of a local phenomenon affecting components of the network than a problem at the system level of networks.
I was a coauthor on a paper cited in this study (Mark et al., 1995). We were not primarily interested in seizures. Rather, our idea was that excitotoxicity would stress neuroplastic mechanisms (possibly involving GSK3) and exacerbate Alzheimer pathology development—which might in turn be reduced by valproate. Valproate seemed potentially useful because it is known to affect the brain. Along these lines, it could be considered that β amyloid could increase the excitability in neural networks, and reduction of that excitability could reduce the predilection for tauopathy to develop. We clearly need more data. At this point, it still remains doubtful to me that that increase of excitability is the hallmark of the amyloid pathologic mechanism.
Teter B, Ashford JW. Neuroplasticity in Alzheimer's disease. J Neurosci Res. 2002 Nov 1;70(3):402-37. PubMed.
Piecoro LT, Wermeling DP, Schmitt FA, Ashford JW. Seizures in patients receiving concomitant antimuscarinics and acetylcholinesterase inhibitor. Pharmacotherapy. 1998 Sep-Oct;18(5):1129-32. PubMed.
Mark RJ, Ashford JW, Goodman Y, Mattson MP. Anticonvulsants attenuate amyloid beta-peptide neurotoxicity, Ca2+ deregulation, and cytoskeletal pathology. Neurobiol Aging. 1995 Mar-Apr;16(2):187-98. PubMed.
Gladstone Institutes and University of California, San Francisco
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.
Amatniek JC, Hauser WA, DelCastillo-Castaneda C, Jacobs DM, Marder K, Bell K, Albert M, Brandt J, Stern Y. Incidence and predictors of seizures in patients with Alzheimer's disease. Epilepsia. 2006 May;47(5):867-72. PubMed.
Edwards-Lee T, Ringman JM, Chung J, Werner J, Morgan A, St George Hyslop P, Thompson P, Dutton R, Mlikotic A, Rogaeva E, Hardy J. An African American family with early-onset Alzheimer disease and an APP (T714I) mutation. Neurology. 2005 Jan 25;64(2):377-9. PubMed.
Hauser WA, Morris ML, Heston LL, Anderson VE. Seizures and myoclonus in patients with Alzheimer's disease. Neurology. 1986 Sep;36(9):1226-30. PubMed.
Hesdorffer DC, Hauser WA, Annegers JF, Kokmen E, Rocca WA. Dementia and adult-onset unprovoked seizures. Neurology. 1996 Mar;46(3):727-30. PubMed.
Larner AJ, Doran M. Clinical phenotypic heterogeneity of Alzheimer's disease associated with mutations of the presenilin-1 gene. J Neurol. 2006 Feb;253(2):139-58. PubMed.
Lozsadi DA, Larner AJ. Prevalence and causes of seizures at the time of diagnosis of probable Alzheimer's disease. Dement Geriatr Cogn Disord. 2006;22(2):121-4. PubMed.
Marcon G, Giaccone G, Cupidi C, Balestrieri M, Beltrami CA, Finato N, Bergonzi P, Sorbi S, Bugiani O, Tagliavini F. Neuropathological and clinical phenotype of an Italian Alzheimer family with M239V mutation of presenilin 2 gene. J Neuropathol Exp Neurol. 2004 Mar;63(3):199-209. PubMed.
Mendez MF, Catanzaro P, Doss RC, ARguello R, Frey WH. Seizures in Alzheimer's disease: clinicopathologic study. J Geriatr Psychiatry Neurol. 1994 Oct-Dec;7(4):230-3. PubMed.
Mendez M, Lim G. Seizures in elderly patients with dementia: epidemiology and management. Drugs Aging. 2003;20(11):791-803. PubMed.
Rabinowicz AL, Starkstein SE, Leiguarda RC, Coleman AE. Transient epileptic amnesia in dementia: a treatable unrecognized cause of episodic amnestic wandering. Alzheimer Dis Assoc Disord. 2000 Oct-Dec;14(4):231-3. 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.
Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P. Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci. 2005 Aug;8(8):1051-8. PubMed.View all comments by Jorge Palop
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.
Kim DY, Carey BW, Wang H, Ingano LA, Binshtok AM, Wertz MH, Pettingell WH, He P, Lee VM, Woolf CJ, Kovacs DM. BACE1 regulates voltage-gated sodium channels and neuronal activity. Nat Cell Biol. 2007 Jul;9(7):755-64. PubMed.View all comments by Michael King
Massachusetts General Hospital
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.
Kim DY, Carey BW, Wang H, Ingano LA, Binshtok AM, Wertz MH, Pettingell WH, He P, Lee VM, Woolf CJ, Kovacs DM. BACE1 regulates voltage-gated sodium channels and neuronal activity. Nat Cell Biol. 2007 Jul;9(7):755-64. PubMed.
Meisler MH, Kearney JA. Sodium channel mutations in epilepsy and other neurological disorders. J Clin Invest. 2005 Aug;115(8):2010-7. PubMed.
Yu FH, Mantegazza M, Westenbroek RE, Robbins CA, Kalume F, Burton KA, Spain WJ, McKnight GS, Scheuer T, Catterall WA. Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nat Neurosci. 2006 Sep;9(9):1142-9. PubMed.
Zhao J, Fu Y, Yasvoina M, Shao P, Hitt B, O'Connor T, Logan S, Maus E, Citron M, Berry R, Binder L, Vassar R. Beta-site amyloid precursor protein cleaving enzyme 1 levels become elevated in neurons around amyloid plaques: implications for Alzheimer's disease pathogenesis. J Neurosci. 2007 Apr 4;27(14):3639-49. PubMed.View all comments by Doo Yeon Kim
This article raises a number of interesting issues with regard to improving the understanding and treatment of Alzheimer disease (AD). The authors demonstrate that β amyloid aberrantly increased neuronal excitability in cortex and hippocampus, which led to a series of neuronal structural and electrophysiologic alterations in the entorhinal cortex and hippocampus that are found in AD pathology. Such β amyloid-induced changes were either genetically induced in transgenic mouse models of AD, or exogenously induced by kainic acid administration in non-transgenic mice. Furthermore, reduction of neuronal tau structural microtubular proteins reduced the amount of disruption. The authors also showed that these animals exhibited abnormal excitatory EEG activity from cortical and hippocampal electrodes, often without clinically overt seizure activity.
The relevance of these basic research findings to treatment of AD patients is that EEG activity may be a useful marker for the expression and treatment-mediated control of these pathophysiologic changes. The EEG signature from scalp electrodes will certainly appear different from that produced by cortical and hippocampal electrodes, as well as from that produced by hippocampal slice recordings. Even so, there is almost certain to be a scalp signature that can be identified with the appropriate EEG analytical methodology (Sneddon et al., 2005). The nature of the scalp EEG signature could be studied by performing scalp recordings in animals who have also had cortical and hippocampal recordings, and by performing hippocampal and cortical plus scalp electrode recordings in AD or perhaps epileptic patients.
Such a scalp EEG signature, once identified by proper EEG analytic methodology, would serve as a useful index of how well a given treatment is retarding AD pathophysiology. This is particularly relevant now that clinically safe β amyloid-lowering agents have been developed and may be FDA-approved soon. While reversal of cognitive and functional impairment in AD would be optimal, it is much more likely that treatment will delay or perhaps halt AD progression, such that an EEG measure of the degree to which this occurs could help guide physicians in optimizing each patient's treatment.
Such an EEG tool would certainly be useful in deciding whether to continue therapy with memantine (Namenda) and with cholinesterase inhibitors in very mildly impaired AD patients. In many cases, there is no clear symptomatic improvement. Because evidence exists both for and against disease-delaying effects for cholinesterase inhibitors (Farlow et al., 2005; Geldmacher et al., 2006; Doody et al., 2001; Raskind et al., 2004; Birks et al., 2006) and for NMDA receptor modulators (i.e., memantine) (Kirby et al., 2006; Bullock 2006), it is useful to identify potential disease-delaying effects in each patient. Given findings by Palop et al. about aberrant neuronal excitatory activity contributing to the progression of AD pathophysiology, it would be important to know if memantine, which minimizes aberrant excitatory glutamatergic activity and may reduce the formation of abnormally phosphorylated tau protein (Degerman Gunnarsson et al., 2007), is forestalling the progression of AD pathophysiology even if symptoms do not improve. Similarly, given the recent findings that cholinesterase inhibitors can beneficially modulate amyloid precursor protein metabolism to potentially reduce β amyloid formation in AD (Nordberg, 2006), and that the three FDA-approved cholinesterase inhibitors have different mechanisms and different potencies in this regard, it would be useful to be able to measure the effect of a given cholinesterase inhibitor on the AD pathophysiology of a given patient. Such translational research from cortical and hippocampal electrophysiology to scalp EEG recordings could have substantial benefits for AD patients and their treating physicians.
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