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Brivaracetam, but not ethosuximide, reverses memory impairments in an Alzheimer's disease mouse model.

Nygaard HB, Kaufman AC, Sekine-Konno T, Huh LL, Going H, Feldman SJ, Kostylev MA, Strittmatter SM - Alzheimers Res Ther (2015)

Bottom Line: The antiepileptic drugs ethosuximide and brivaracetam were tested for their ability to suppress epileptiform activity and to reverse memory impairments and synapse loss in APP/PS1 mice.Our data confirm an intriguing therapeutic role of anticonvulsant drugs targeting synaptic vesicle protein 2A across AD mouse models.Chronic ethosuximide dosing did not reverse spatial memory impairments in APP/PS1 mice, despite reduction of SWDs.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Yale University School of Medicine, 800 Howard Avenue, New Haven, CT 06510 USA ; Cellular Neuroscience, Neurodegeneration, and Repair Program (CNNR), Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536 USA ; Division of Neurology, The University of British Columbia, Djavad Mowafaghian Centre for Brain Health, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z3 Canada.

ABSTRACT

Introduction: Recent studies have shown that several strains of transgenic Alzheimer's disease (AD) mice overexpressing the amyloid precursor protein (APP) have cortical hyperexcitability, and their results have suggested that this aberrant network activity may be a mechanism by which amyloid-β (Aβ) causes more widespread neuronal dysfunction. Specific anticonvulsant therapy reverses memory impairments in various transgenic mouse strains, but it is not known whether reduction of epileptiform activity might serve as a surrogate marker of drug efficacy for memory improvement in AD mouse models.

Methods: Transgenic AD mice (APP/PS1 and 3xTg-AD) were chronically implanted with dural electroencephalography electrodes, and epileptiform activity was correlated with spatial memory function and transgene-specific pathology. The antiepileptic drugs ethosuximide and brivaracetam were tested for their ability to suppress epileptiform activity and to reverse memory impairments and synapse loss in APP/PS1 mice.

Results: We report that in two transgenic mouse models of AD (APP/PS1 and 3xTg-AD), the presence of spike-wave discharges (SWDs) correlated with impairments in spatial memory. Both ethosuximide and brivaracetam reduce mouse SWDs, but only brivaracetam reverses memory impairments in APP/PS1 mice.

Conclusions: Our data confirm an intriguing therapeutic role of anticonvulsant drugs targeting synaptic vesicle protein 2A across AD mouse models. Chronic ethosuximide dosing did not reverse spatial memory impairments in APP/PS1 mice, despite reduction of SWDs. Our data indicate that SWDs are not a reliable surrogate marker of appropriate target engagement for reversal of memory dysfunction in APP/PS1 mice.

No MeSH data available.


Related in: MedlinePlus

The presence of spike wave discharges is not associated with changes in amyloid precursor protein metabolism or amyloid-β levels. In APP/PS1 mice, the presence of spike-wave discharges (SWDs) did not alter levels of soluble amyloid precursor protein (sAPP)-α (100 kDa marker), β-C-terminal fragment (β-CTF) (15 kDa marker) or amyloid-β (Aβ) monomers (5 kDa marker) by Western blot analysis (A, D). Actin loading control is indicated by the 37 kDa marker. In the same strain, Aβ plaque deposits were not altered by the presence of SWDs (B, C, E). Similarly, in 3xTg-AD mice, the presence of SWDs did not alter levels of sAPP-α or β-CTF as analyzed by Western blotting (F, I), nor did it alter levels of Aβ plaque (G, H, J). Data were analyzed by two-tailed Student’s t-test. APP/PS1, n = 11; 3xTg-AD, n = 11. +Indicates the presence of SWDs, and − indicates no SWDs. HC, Hippocampus; C, Cortex; PSEN, Presenelin; WT, Wild type.
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Fig3: The presence of spike wave discharges is not associated with changes in amyloid precursor protein metabolism or amyloid-β levels. In APP/PS1 mice, the presence of spike-wave discharges (SWDs) did not alter levels of soluble amyloid precursor protein (sAPP)-α (100 kDa marker), β-C-terminal fragment (β-CTF) (15 kDa marker) or amyloid-β (Aβ) monomers (5 kDa marker) by Western blot analysis (A, D). Actin loading control is indicated by the 37 kDa marker. In the same strain, Aβ plaque deposits were not altered by the presence of SWDs (B, C, E). Similarly, in 3xTg-AD mice, the presence of SWDs did not alter levels of sAPP-α or β-CTF as analyzed by Western blotting (F, I), nor did it alter levels of Aβ plaque (G, H, J). Data were analyzed by two-tailed Student’s t-test. APP/PS1, n = 11; 3xTg-AD, n = 11. +Indicates the presence of SWDs, and − indicates no SWDs. HC, Hippocampus; C, Cortex; PSEN, Presenelin; WT, Wild type.

Mentions: Having shown that the presence of SWDs correlates with impairments in spatial memory, we assessed whether SWDs also impact biochemical and histologic measures in transgenic AD brain, including APP metabolites and Aβ levels. Immunoblotting of soluble and detergent extracts of brain homogenates revealed no correlation between SWDs and levels of soluble APP-α, β-C-terminal fragment or Aβ in APP/PS1 or 3xTg-AD mice (Figure 3A,D,F,I). In addition, neither cortical nor hippocampal deposits of insoluble Aβ plaque differed with regard to the presence of SWDs in APP/PS1 mice (Figure 3B,C,E). Although no cortical plaques were seen in 3xTg mice at 8 to 10 months of age, the presence or absence of SWDs was not associated with hippocampal plaque density in these mice (Figure 3G,H,J). Hippocampal calbindin D-28K was first reported to be reduced in human AD several decades ago [19] and plays a role in normal hippocampal physiology as an intracellular calcium buffer [20]. Its link to epilepsy comes from the finding that patients with epilepsy have a loss of calbindin D28 in several areas of the hippocampus, and these changes have been proposed to affect the plasticity changes associated with the maintenance of the epileptic phenotype [21]. In studies in the J20 model of AD, researchers have reported a decrease in hippocampal calbindin D28 in the hippocampus, which is thought to reflect neuronal hyperexcitability [4]. In contrast to studies in J20 mice, in our present study we did not detect a reduction of calbindin D28 in APP/PS1 mice compared with WT littermates (data not shown).Figure 3


Brivaracetam, but not ethosuximide, reverses memory impairments in an Alzheimer's disease mouse model.

Nygaard HB, Kaufman AC, Sekine-Konno T, Huh LL, Going H, Feldman SJ, Kostylev MA, Strittmatter SM - Alzheimers Res Ther (2015)

The presence of spike wave discharges is not associated with changes in amyloid precursor protein metabolism or amyloid-β levels. In APP/PS1 mice, the presence of spike-wave discharges (SWDs) did not alter levels of soluble amyloid precursor protein (sAPP)-α (100 kDa marker), β-C-terminal fragment (β-CTF) (15 kDa marker) or amyloid-β (Aβ) monomers (5 kDa marker) by Western blot analysis (A, D). Actin loading control is indicated by the 37 kDa marker. In the same strain, Aβ plaque deposits were not altered by the presence of SWDs (B, C, E). Similarly, in 3xTg-AD mice, the presence of SWDs did not alter levels of sAPP-α or β-CTF as analyzed by Western blotting (F, I), nor did it alter levels of Aβ plaque (G, H, J). Data were analyzed by two-tailed Student’s t-test. APP/PS1, n = 11; 3xTg-AD, n = 11. +Indicates the presence of SWDs, and − indicates no SWDs. HC, Hippocampus; C, Cortex; PSEN, Presenelin; WT, Wild type.
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Fig3: The presence of spike wave discharges is not associated with changes in amyloid precursor protein metabolism or amyloid-β levels. In APP/PS1 mice, the presence of spike-wave discharges (SWDs) did not alter levels of soluble amyloid precursor protein (sAPP)-α (100 kDa marker), β-C-terminal fragment (β-CTF) (15 kDa marker) or amyloid-β (Aβ) monomers (5 kDa marker) by Western blot analysis (A, D). Actin loading control is indicated by the 37 kDa marker. In the same strain, Aβ plaque deposits were not altered by the presence of SWDs (B, C, E). Similarly, in 3xTg-AD mice, the presence of SWDs did not alter levels of sAPP-α or β-CTF as analyzed by Western blotting (F, I), nor did it alter levels of Aβ plaque (G, H, J). Data were analyzed by two-tailed Student’s t-test. APP/PS1, n = 11; 3xTg-AD, n = 11. +Indicates the presence of SWDs, and − indicates no SWDs. HC, Hippocampus; C, Cortex; PSEN, Presenelin; WT, Wild type.
Mentions: Having shown that the presence of SWDs correlates with impairments in spatial memory, we assessed whether SWDs also impact biochemical and histologic measures in transgenic AD brain, including APP metabolites and Aβ levels. Immunoblotting of soluble and detergent extracts of brain homogenates revealed no correlation between SWDs and levels of soluble APP-α, β-C-terminal fragment or Aβ in APP/PS1 or 3xTg-AD mice (Figure 3A,D,F,I). In addition, neither cortical nor hippocampal deposits of insoluble Aβ plaque differed with regard to the presence of SWDs in APP/PS1 mice (Figure 3B,C,E). Although no cortical plaques were seen in 3xTg mice at 8 to 10 months of age, the presence or absence of SWDs was not associated with hippocampal plaque density in these mice (Figure 3G,H,J). Hippocampal calbindin D-28K was first reported to be reduced in human AD several decades ago [19] and plays a role in normal hippocampal physiology as an intracellular calcium buffer [20]. Its link to epilepsy comes from the finding that patients with epilepsy have a loss of calbindin D28 in several areas of the hippocampus, and these changes have been proposed to affect the plasticity changes associated with the maintenance of the epileptic phenotype [21]. In studies in the J20 model of AD, researchers have reported a decrease in hippocampal calbindin D28 in the hippocampus, which is thought to reflect neuronal hyperexcitability [4]. In contrast to studies in J20 mice, in our present study we did not detect a reduction of calbindin D28 in APP/PS1 mice compared with WT littermates (data not shown).Figure 3

Bottom Line: The antiepileptic drugs ethosuximide and brivaracetam were tested for their ability to suppress epileptiform activity and to reverse memory impairments and synapse loss in APP/PS1 mice.Our data confirm an intriguing therapeutic role of anticonvulsant drugs targeting synaptic vesicle protein 2A across AD mouse models.Chronic ethosuximide dosing did not reverse spatial memory impairments in APP/PS1 mice, despite reduction of SWDs.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Yale University School of Medicine, 800 Howard Avenue, New Haven, CT 06510 USA ; Cellular Neuroscience, Neurodegeneration, and Repair Program (CNNR), Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536 USA ; Division of Neurology, The University of British Columbia, Djavad Mowafaghian Centre for Brain Health, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z3 Canada.

ABSTRACT

Introduction: Recent studies have shown that several strains of transgenic Alzheimer's disease (AD) mice overexpressing the amyloid precursor protein (APP) have cortical hyperexcitability, and their results have suggested that this aberrant network activity may be a mechanism by which amyloid-β (Aβ) causes more widespread neuronal dysfunction. Specific anticonvulsant therapy reverses memory impairments in various transgenic mouse strains, but it is not known whether reduction of epileptiform activity might serve as a surrogate marker of drug efficacy for memory improvement in AD mouse models.

Methods: Transgenic AD mice (APP/PS1 and 3xTg-AD) were chronically implanted with dural electroencephalography electrodes, and epileptiform activity was correlated with spatial memory function and transgene-specific pathology. The antiepileptic drugs ethosuximide and brivaracetam were tested for their ability to suppress epileptiform activity and to reverse memory impairments and synapse loss in APP/PS1 mice.

Results: We report that in two transgenic mouse models of AD (APP/PS1 and 3xTg-AD), the presence of spike-wave discharges (SWDs) correlated with impairments in spatial memory. Both ethosuximide and brivaracetam reduce mouse SWDs, but only brivaracetam reverses memory impairments in APP/PS1 mice.

Conclusions: Our data confirm an intriguing therapeutic role of anticonvulsant drugs targeting synaptic vesicle protein 2A across AD mouse models. Chronic ethosuximide dosing did not reverse spatial memory impairments in APP/PS1 mice, despite reduction of SWDs. Our data indicate that SWDs are not a reliable surrogate marker of appropriate target engagement for reversal of memory dysfunction in APP/PS1 mice.

No MeSH data available.


Related in: MedlinePlus