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Review
. 2017 Jul;14(3):662-676.
doi: 10.1007/s13311-017-0541-z.

Targeting Neural Hyperactivity as a Treatment to Stem Progression of Late-Onset Alzheimer's Disease

Rebecca P Haberman  1 , Audrey Branch  2 , Michela Gallagher  2
Affiliations
Review

Targeting Neural Hyperactivity as a Treatment to Stem Progression of Late-Onset Alzheimer's Disease

Rebecca P Haberman et al. Neurotherapeutics. 2017 Jul.

Abstract

Sporadic late-onset Alzheimer's disease (LOAD), the most common form of dementia in the elderly, causes progressive and severe loss of cognitive abilities. With greater numbers of people living to advanced ages, LOAD will increasingly burden both the healthcare system and society. There are currently no available disease-modifying therapies, and the failure of several recent pathology-based strategies has highlighted the urgent need for effective therapeutic targets. With aging as the greatest risk factor for LOAD, targeting mechanisms by which aging contributes to disease could prove an effective strategy to delay progression to clinical dementia by intervention in elderly individuals in an early prodromal stage of disease. Excess neural activity in the hippocampus, a recently described phenomenon associated with age-dependent memory loss, was first identified in animal models of aging and subsequently translated to clinical conditions of aging and early-stage LOAD. Critically, elevated activity was similarly localized to specific circuits within the hippocampal formation in aged animals and humans. Here we review evidence for hippocampal hyperactivity as a significant contributor to age-dependent cognitive decline and the progressive accumulation of pathology in LOAD. We also describe studies demonstrating the efficacy of reducing hyperactivity with an initial test therapy, levetiracetam (Keppra), an atypical antiepileptic. By targeting excess neural activity, levetiracetam may improve cognition and attenuate the accumulation of pathology contributing to progression to the dementia phase of LOAD.

Keywords: Amnestic mild cognitive impairment (aMCI); Cognitive aging; Hippocampal CA3; Late-onset Alzheimer’s disease; Levetiracetam (Keppra).

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Figures

Fig. 1
Fig. 1
Schematic of connectional pathways. The perforant path (PP) from entorhinal cortex (EC) layer 2 cells provides innervation of the dentate gyrus (DG) and CA3. CA3 pyramidal neurons also receive synaptic input from DG mossy fibers and CA3 recurrent collaterals. The output of the DG/CA3 computational processing occurs through the CA1 subfield and the subiculum (not shown) projecting to deep layers of the EC and additional cortical structures
Fig. 2
Fig. 2
Pharmacologically induced neural activity is elevated in aged rats with memory impairment and reduced by levetiracetam (LEV) treatment. Neural activity was pharmacologically induced (pilocarpine, 25 mg/kg i.p.) in young (Y), aged rats with intact memory (aged unimpaired, AU) and aged impaired rats (AI). Induced neural activity was detected by quantification of cFos mRNA by in situ hybridization of brain sections collected 1 h after induction. (A) CA3 subfield of the hippocampus shows higher expression of cFos in AI rats compared with Y and AU rats. cFos expression also correlates with a measure of memory impairment among all aged rats (Pearson r = 0.832). AI rats also showed increased cFos in retrosplenial (RSC) and parietal cortex (PC) relative to both AU and Y rats (data not shown). (B) AI rats in the LEV condition (AI-LEV) were treated for 1 month prior to pilocarpine administration with LEV via osmotic pumps (10 mg/kg/day). Treatment with LEV reduced cFos expression in AI rats in the CA3 region of the hippocampus and select interconnected regions, including RSC and PC. ACC and thalamus show no impairment-dependent elevation of cFos and no reduction with LEV treatment. Significant difference across groups was determined by 1-way analysis of variance. Post-hoc significance was determined by t test as indicted on the graphs: *p < 0.05; **p < 0.01. Values represent group means ± SEM. Gray dotted line represents cFos expression in young rats. Figure adapted from Neurobiology of Aging, Haberman, RP, Koh, MT, and Gallagher, M, Heightened Cortical Excitability in Aged Rodents with Memory Impairment, in press, Copyright 2017) and reprinted with permission from Elsevier [22]. ACC = anterior cingulate cortex
Fig. 3
Fig. 3
High-resolution functional magnetic resonance imaging signals in amnestic mild cognitive impairment (aMCI) vs age-matched controls. Patients with aMCI had significantly higher task-related activation in the left CA3 (LCA3)/dentage gyrus (DG) together with lower activity in the left entorhinal cortex (LERC) during encoding for similar items on 3-judgement task. * aMCI significantly different from controls. Figure reprinted from Neuroimage, 51, Yassa, MA, Stark, SM, Bakker, A, Albert, MS, Gallagher, M and Stark, CEL, High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with amnestic Mild Cognitive Impairment, 1242-1252, Copyright (2010) with permission from Elsevier [15]. LCA1 = left CA1; LSUB = left subiculum
Fig. 4
Fig. 4
Alterations coinciding with hippocampal hyperactivity and memory impairment. (A) Schematic illustrating the reduction of Reelin expression in entorhinal cortex (EC) layer 2 and somatostatin (SOM) expression in the dentate hilus interneurons in age-related memory impairment. (B) These data replicate the findings in Stranahan et al. [122] of reduced reelin mRNA in EC layer II neurons of aged impaired (AI) rats and its reversal in AI rats treated with levetiracetam (LEV) by osmotic minipump (10 mg/kg/day) for 28 days (figure panel provided by Koh, MT and Gallagher, M); *p < 0.05. (C) Somatostatin expression in dentate hilus interneurons is reduced in AI rats and rescued by the same osmotic minipump treatment with LEV; *p < 0.05. Part (C) adapted from Spiegel, A.M., Koh, M.T., Vogt, N.M., Rapp, P.R., & Gallagher, M. Journal of Comparative Neurology vol 521, p. 3508-3523. Copyright (2013) reprinted with permission from John Wiley and Sons [128]. DG = dentate gyrus; YNG = young; AI-VEH = AI rats treated with saline vehicle; AI-LEV = AI rats treated with LEV
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