Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Ho K, Yu GQ, Palop JJ, Mucke L. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model. Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):E2895-903. PubMed.
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Massachusetts General Hospital
This new study by Dr. Mucke and colleagues provides a great deal of important data to support the hypotheses that 1) abnormalities of neural network function are important contributors to behavioral deficits in mouse models of AD; 2) targeting these physiologic/functional abnormalities with specific treatments can ameliorate behavioral deficits; 3) such treatment does not appear to affect traditional histological markers of AD. These results, in conjunction with a series of other findings in the field (most importantly, Bakker et al., 2012), make a strong case for the need for further studies of physiologic neural network-level abnormalities in AD and related disorders, and also for the targeting of these abnormalities for novel approaches to treatment.
References:
Bakker A, Krauss GL, Albert MS, Speck CL, Jones LR, Stark CE, Yassa MA, Bassett SS, Shelton AL, Gallagher M. Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron. 2012 May 10;74(3):467-74. PubMed.
Johns Hopkins University
This report by Sanchez et al. demonstrating improvements in molecular markers, synaptic function, and memory performance in hAPP mice points to overactivity as a therapeutic target. These data from a preclinical model of AD also match recent results from a study of amnestic mild cognitive impairment (aMCI) patients treated with the same therapeutic. In both cases, preclinical and clinical, targeting overactivity was an effective treatment. Such translation across a preclinical AD model and clinical patients is rare, if not unprecedented, in the AD field. The clinical results reported recently by us (Bakker et al., 2012) showed that neural network overactivity detected by functional magnetic resonance imaging (fMRI) was reduced in aMCI by a subclinical dose of levetiracetam, and concomitantly improved performance on a memory task. In the case of the physiological experiments in AD mice, which would not be possible in humans, multiple sites of synaptic dysfunction in the affected network were resolved, including reduced effective synaptic connections (e.g., in CA1 of hippocampus), consistent with the authors' view that synaptic remodeling is driven, at least in part, by overactivity rather than the other way around.
The condition of overactivity treated in aMCI patients may be considerably more subtle than the aberrant activity occurring in J20 hAPP mice, and other mouse models based on familial AD. Indeed, the window of therapeutic efficacy, at subclinical doses of levetiracetam, is unlikely to be attributable to or aligned with anti-epileptic efficacy across the spectrum beginning with age-related memory loss and continuing to MCI and AD. A model of memory loss in aged outbred rats originally led to the discovery that neurons in the CA3 subregion of the hippocampus have elevated firing rates (Wilson et al., 2005). The CA3/CA1 synaptic connections in those animals also exhibit a compensatory profile (Nicholson et al., 2004) showing some additional similarity with the network remodeling occurring in AD mice. In contrast with the AD mice, however, no evidence of aberrant activity occurs in that condition of aging, based on extensive recordings from neurons and EEG monitoring. The fMRI studies of aMCI patients, guided by the studies of network dysfunction in aging, also closely resemble the findings from aged rats with memory loss, showing a localization of excess activation confined to the CA3/dentate gyrus (Yassa et al., 2010; Bakker et al., 2012). The more widespread and pathological aberrant activity in certain AD models may represent one end of a continuum in understanding how aging and the emergence of AD pathology affect the brain in the majority of late-onset cases.
References:
Bakker A, Krauss GL, Albert MS, Speck CL, Jones LR, Stark CE, Yassa MA, Bassett SS, Shelton AL, Gallagher M. Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron. 2012 May 10;74(3):467-74. PubMed.
Nicholson DA, Yoshida R, Berry RW, Gallagher M, Geinisman Y. Reduction in size of perforated postsynaptic densities in hippocampal axospinous synapses and age-related spatial learning impairments. J Neurosci. 2004 Sep 1;24(35):7648-53. PubMed.
Wilson IA, Ikonen S, Gallagher M, Eichenbaum H, Tanila H. Age-associated alterations of hippocampal place cells are subregion specific. J Neurosci. 2005 Jul 20;25(29):6877-86. PubMed.
Yassa MA, Stark SM, Bakker A, Albert MS, Gallagher M, Stark CE. High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with amnestic Mild Cognitive Impairment. Neuroimage. 2010 Jul 1;51(3):1242-52. PubMed.
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