Generic placeholder image

Current Alzheimer Research


ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Research Article

Pregabalin Treatment does not Affect Amyloid Pathology in 5XFAD Mice

Author(s): Katherine R. Sadleir*, Jelena Popovoic, Wei Zhu, Cory T. Reidel, Ha Do, Richard B. Silverman and Robert Vassar

Volume 18, Issue 4, 2021

Published on: 08 September, 2021

Page: [283 - 297] Pages: 15

DOI: 10.2174/1567205018666210713125333

open access plus


Background: Calcium dysregulation has been proposed to play a causative role in the development of Alzheimer’s disease pathology. Pregabalin is a compound already approved for human use, marketed as the prescription drug Lyrica. It binds the α2-δ subunit of P/Q-type voltagegated calcium channels, lowering calcium influx and providing effective treatment for epilepsy and neuropathic pain.

Objective: We hypothesize that increased resting calcium in neuronal processes near amyloid plaques plays a role in the development of neuritic dystrophies and further progression of amyloid pathology.

Methods: 5XFAD mice were treated orally for 12 weeks with pregabalin, then immunoblotting and immunofluorescent imaging were used to quantify neuritic dystrophy and amyloid deposition in pregabalin compared to placebo-treated mice.

Results: The treatment did not decrease markers of neuritic dystrophy or amyloid deposition. The image analysis of neuritic dystrophy on a plaque-by-plaque basis showed a small non-significant increase in the relative proportion of LAMP1 to Aβ42 in plaques with areas of 50-450 μm2 in the cortex of pregabalin-treated mice. In addition, there was a statistically significant positive correlation between the measured cerebral concentration of pregabalin and the relative levels of BACE1 and Aβ in the cortex. This relationship was not observed in the hippocampus, and there was no increase in average Aβ levels in pregabalin treated mice compared to placebo. We confirmed previous findings that smaller amyloid plaques are associated with a greater degree of neuritic dystrophy.

Conclusion: Pregabalin may have an effect on Aβ that merits further investigation, but our study does not suggest that pregabalin contributes substantially to amyloid pathology.

Keywords: Alzheimer's, amyloid, pregabalin, synthesis, BACE1, dystrophic neurites, calcium, 5XFAD.

Elmaleh DR, Farlow MR, Conti PS, Tompkins RG, Kundakovic L, Tanzi RE. Developing effective Alzheimer’s disease therapies: Clinical experience and future directions. J Alzheimers Dis 2019; 71(3): 715-32.
[] [PMID: 31476157]
Long JM, Holtzman DM. Alzheimer disease: An update on pathobiology and treatment strategies. Cell 2019; 179(2): 312-39.
[] [PMID: 31564456]
Hussain I, Powell D, Howlett DR, et al. Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci 1999; 14(6): 419-27.
[] [PMID: 10656250]
Sinha S, Anderson JP, Barbour R, et al. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 1999; 402(6761): 537-40.
[] [PMID: 10591214]
Vassar R, Bennett BD, Babu-Khan S, et al. Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999; 286(5440): 735-41.
[] [PMID: 10531052]
Yan R, Bienkowski MJ, Shuck ME, et al. Membrane-anchored aspartyl protease with Alzheimer’s disease beta-secretase activity. Nature 1999; 402(6761): 533-7.
[] [PMID: 10591213]
Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 2016; 8(6): 595-608.
[] [PMID: 27025652]
8 Khachaturian ZS. Towards theories of brain aging. In: Handbook of studies on psychiatry and old age. Amsterdam: Elsevier Science Publishers B.V. 1984; pp. 7-30.
9 Alzheimer's Association calcium Hypothesis Workgroup. Calcium hypothesis of Alzheimer's disease and brain aging: A framework for integrating new evidence into a comprehensive theory of pathogenesis. Alzheimers Dement 2017; 13(2): 178-82 e17.
Alberdi E, Sánchez-Gómez MV, Cavaliere F, et al. Amyloid beta oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptors. Cell Calcium 2010; 47(3): 264-72.
[] [PMID: 20061018]
Demuro A, Mina E, Kayed R, Milton SC, Parker I, Glabe CG. Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. J Biol Chem 2005; 280(17): 17294-300.
[] [PMID: 15722360]
Nimmrich V, Grimm C, Draguhn A, et al. Amyloid beta oligomers (A beta(1-42) globulomer) suppress spontaneous synaptic activity by inhibition of P/Q-type calcium currents. J Neurosci 2008; 28(4): 788-97.
[] [PMID: 18216187]
Kuchibhotla KV, Goldman ST, Lattarulo CR, Wu HY, Hyman BT, Bacskai BJ. Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. Neuron 2008; 59(2): 214-25.
[] [PMID: 18667150]
Busche MA, Chen X, Henning HA, et al. Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 2012; 109(22): 8740-5.
[] [PMID: 22592800]
Busche MA, Eichhoff G, Adelsberger H, et al. Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease. Science 2008; 321(5896): 1686-9.
[] [PMID: 18802001]
Sadleir KR, Kandalepas PC, Buggia-Prévot V, Nicholson DA, Thinakaran G, Vassar R. Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased Aβ generation in Alzheimer’s disease. Acta Neuropathol 2016; 132(2): 235-56.
[] [PMID: 26993139]
Fukumoto H, Cheung BS, Hyman BT, Irizarry MC. Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol 2002; 59(9): 1381-9.
[] [PMID: 12223024]
Holsinger RMD, McLean CA, Beyreuther K, Masters CL, Evin G. Increased expression of the amyloid precursor beta-secretase in Alzheimer’s disease. Ann Neurol 2002; 51(6): 783-6.
[] [PMID: 12112088]
Li R, Lindholm K, Yang LB, et al. Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer’s disease patients. Proc Natl Acad Sci USA 2004; 101(10): 3632-7.
[] [PMID: 14978286]
Yang LB, Lindholm K, Yan R, et al. Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med 2003; 9(1): 3-4.
[] [PMID: 12514700]
Zhao J, Fu Y, Yasvoina M, et al. 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; 27(14): 3639-49.
[] [PMID: 17409228]
Kandalepas PC, Sadleir KR, Eimer WA, Zhao J, Nicholson DA, Vassar R. The Alzheimer’s β-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques. Acta Neuropathol 2013; 126(3): 329-52.
[] [PMID: 23820808]
Yu WH, Cuervo AM, Kumar A, et al. Macroautophagy-a novel Beta-amyloid peptide-generating pathway activated in Alzheimer’s disease. J Cell Biol 2005; 171(1): 87-98.
[] [PMID: 16203860]
Peters F, Salihoglu H, Rodrigues E, et al. BACE1 inhibition more effectively suppresses initiation than progression of β-amyloid pathology. Acta Neuropathol 2018; 135(5): 695-710.
[] [PMID: 29327084]
Rudinskiy N, Hawkes JM, Betensky RA, et al. Orchestrated experience-driven Arc responses are disrupted in a mouse model of Alzheimer’s disease. Nat Neurosci 2012; 15(10): 1422-9.
[] [PMID: 22922786]
Egan MF, Kost J, Tariot PN, et al. Randomized trial of verubecestat for mild-to-moderate alzheimer’s disease. N Engl J Med 2018; 378(18): 1691-703.
[] [PMID: 29719179]
Egan MF, Kost J, Voss T, et al. Randomized trial of verubecestat for prodromal Alzheimer’s disease. N Engl J Med 2019; 380(15): 1408-20.
[] [PMID: 30970186]
Egan MF, Mukai Y, Voss T, et al. Further analyses of the safety of verubecestat in the phase 3 EPOCH trial of mild-to-moderate Alzheimer’s disease. Alzheimers Res Ther 2019; 11(1): 68.
[] [PMID: 31387606]
Adalbert R, Nogradi A, Babetto E, et al. Severely dystrophic axons at amyloid plaques remain continuous and connected to viable cell bodies. Brain 2009; 132(Pt 2): 402-16.
[] [PMID: 19059977]
Blazquez-Llorca L, Valero-Freitag S, Rodrigues EF, et al. High plasticity of axonal pathology in Alzheimer’s disease mouse models. Acta Neuropathol Commun 2017; 5(1): 14.
[] [PMID: 28173876]
Meyer-Luehmann M, Spires-Jones TL, Prada C, et al. Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease. Nature 2008; 451(7179): 720-4.
[] [PMID: 18256671]
Brendza RP, Bacskai BJ, Cirrito JR, et al. Anti-Abeta antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice. J Clin Invest 2005; 115(2): 428-33.
[] [PMID: 15668737]
Silverman RB, Andruszkiewicz R, Nanavati SM, Taylor CP, Vartanian MG. 3-Alkyl-4-aminobutyric acids: The first class of anticonvulsant agents that activates L-glutamic acid decarboxylase. J Med Chem 1991; 34(7): 2295-8.
[] [PMID: 2067001]
Bian F, Li Z, Offord J, et al. Calcium channel alpha2-delta type 1 subunit is the major binding protein for pregabalin in neocortex, hippocampus, amygdala, and spinal cord: An ex vivo autoradiographic study in alpha2-delta type 1 genetically modified mice. Brain Res 2006; 1075(1): 68-80.
[] [PMID: 16460711]
Gee NS, Brown JP, Dissanayake VU, Offord J, Thurlow R, Woodruff GN. The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel. J Biol Chem 1996; 271(10): 5768-76.
[] [PMID: 8621444]
Cole RL, Lechner SM, Williams ME, et al. Differential distribution of voltage-gated calcium channel alpha-2 delta (alpha2delta) subunit mRNA-containing cells in the rat central nervous system and the dorsal root ganglia. J Comp Neurol 2005; 491(3): 246-69.
[] [PMID: 16134135]
Nieto-Rostro M, Sandhu G, Bauer CS, Jiruska P, Jefferys JG, Dolphin AC. Altered expression of the voltage-gated calcium channel subunit α 2 δ-1: A comparison between two experimental models of epilepsy and a sensory nerve ligation model of neuropathic pain. Neuroscience 2014; 283: 124-37.
[] [PMID: 24641886]
Bauer CS, Nieto-Rostro M, Rahman W, et al. The increased trafficking of the calcium channel subunit alpha2delta-1 to presynaptic terminals in neuropathic pain is inhibited by the alpha2delta ligand pregabalin. J Neurosci 2009; 29(13): 4076-88.
[] [PMID: 19339603]
Taylor CP, Garrido R. Immunostaining of rat brain, spinal cord, sensory neurons and skeletal muscle for calcium channel alpha2-delta (alpha2-delta) type 1 protein. Neuroscience 2008; 155(2): 510-21.
[] [PMID: 18616987]
Dolphin AC. The α2δ subunits of voltage-gated calcium channels. Biochim Biophys Acta 2013; 1828(7): 1541-9.
[] [PMID: 23196350]
Taylor CP, Angelotti T, Fauman E. Pharmacology and mechanism of action of pregabalin: The calcium channel alpha2-delta (alpha2-delta) subunit as a target for antiepileptic drug discovery. Epilepsy Res 2007; 73(2): 137-50.
[] [PMID: 17126531]
Hoekstra MS, Sobieray DM, Schwindt MA, et al. Chemical development of CI-1008, an enantiomerically pure anticonvulsant. Org Process Res Dev 1997; 1(1): 26-38.
Oakley H, Cole SL, Logan S, et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: Potential factors in amyloid plaque formation. J Neurosci 2006; 26(40): 10129-40.
[] [PMID: 17021169]
Belliotti TR, Capiris T, Ekhato IV, et al. Structure-activity relationships of pregabalin and analogues that target the alpha(2)-delta protein. J Med Chem 2005; 48(7): 2294-307.
[] [PMID: 15801823]
U. S. Food and Drug Administration CfDEaR. Approval package for application number NDA 21-723, pharmacology/toxicology review and evaluation. 2004.
Mullan M, Crawford F, Axelman K, et al. A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet 1992; 1(5): 345-7.
[] [PMID: 1302033]
Eckman CB, Mehta ND, Crook R, et al. A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A beta 42(43). Hum Mol Genet 1997; 6(12): 2087-9.
[] [PMID: 9328472]
Goate A, Chartier-Harlin MC, Mullan M, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 1991; 349(6311): 704-6.
[] [PMID: 1671712]
Eimer WA, Vassar R. Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Aβ42 accumulation and Caspase-3 activation. Mol Neurodegener 2013; 8: 2.
[] [PMID: 23316765]
Bachmanov AA, Reed DR, Beauchamp GK, Tordoff MG. Food intake, water intake, and drinking spout side preference of 28 mouse strains. Behav Genet 2002; 32(6): 435-43.
[] [PMID: 12467341]
Feng MR, Turluck D, Burleigh J, et al. Brain microdialysis and PK/PD correlation of pregabalin in rats. Eur J Drug Metab Pharmacokinet 2001; 26(1-2): 123-8.
[] [PMID: 11554426]
Ohno M, Chang L, Tseng W, et al. Temporal memory deficits in Alzheimer’s mouse models: Rescue by genetic deletion of BACE1. Eur J Neurosci 2006; 23(1): 251-60.
[] [PMID: 16420434]
Sadleir KR, Eimer WA, Kaufman RJ, Osten P, Vassar R. Genetic inhibition of phosphorylation of the translation initiation factor eIF2α does not block Aβ-dependent elevation of BACE1 and APP levels or reduce amyloid pathology in a mouse model of Alzheimer’s disease. PLoS One 2014; 9(7): e101643.
[] [PMID: 24992504]
Gowrishankar S, Yuan P, Wu Y, et al. Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques. Proc Nat Acad Sci USA 2015; 112(28): E3699-708.
Sadleir KR, Eimer WA, Cole SL, Vassar R. Aβ reduction in BACE1 heterozygous null 5XFAD mice is associated with transgenic APP level. Mol Neurodegener 2015; 10: 1.
[] [PMID: 25567526]
Condello C, Schain A, Grutzendler J. Multicolor time-stamp reveals the dynamics and toxicity of amyloid deposition. Sci Rep 2011; 1: 19.
[] [PMID: 22355538]
Arnold SE, Arvanitakis Z, Macauley-Rambach SL, et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: Concepts and conundrums. Nat Rev Neurol 2018; 14(3): 168-81.
[] [PMID: 29377010]
Taipale H, Gomm W, Broich K, et al. Use of antiepileptic drugs and dementia risk-an analysis of finnish health register and german health insurance data. J Am Geriatr Soc 2018; 66(6): 1123-9.
[] [PMID: 29566430]
Friedman D, Honig LS, Scarmeas N. Seizures and epilepsy in Alzheimer’s disease. CNS Neurosci Ther 2012; 18(4): 285-94.
[] [PMID: 22070283]
Vartanian MG, Radulovic LL, Kinsora JJ, et al. Activity profile of pregabalin in rodent models of epilepsy and ataxia. Epilepsy Res 2006; 68(3): 189-205.
[] [PMID: 16337109]
Qing H, He G, Ly PT, et al. Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimer’s disease mouse models. J Exp Med 2008; 205(12): 2781-9.
[] [PMID: 18955571]
Xuan AG, Pan XB, Wei P, et al. Valproic acid alleviates memory deficits and attenuates amyloid-β deposition in transgenic mouse model of Alzheimer’s disease. Mol Neurobiol 2015; 51(1): 300-12.
[] [PMID: 24854198]
Zeng Q, Long Z, Feng M, et al. Valproic acid stimulates hippocampal neurogenesis via activating the wnt/β-catenin signaling pathway in the APP/PS1/Nestin-GFP triple transgenic mouse model of Alzheimer’s disease. Front Aging Neurosci 2019; 11: 62.
[] [PMID: 30971911]
Owona BA, Zug C, Schluesener HJ, Zhang ZY. Amelioration of behavioral impairments and neuropathology by antiepileptic drug topiramate in a transgenic Alzheimer’s disease model mice, APP/PS1. Int J Mol Sci 2019; 20(12): E3003.
[] [PMID: 31248209]
Li L, Zhang S, Zhang X, et al. Autophagy enhancer carbamazepine alleviates memory deficits and cerebral amyloid-β pathology in a mouse model of Alzheimer’s disease. Curr Alzheimer Res 2013; 10(4): 433-41.
[] [PMID: 23305067]
Shi JQ, Wang BR, Tian YY, et al. Antiepileptics topiramate and levetiracetam alleviate behavioral deficits and reduce neuropathology in APPswe/PS1dE9 transgenic mice. CNS Neurosci Ther 2013; 19(11): 871-81.
[] [PMID: 23889921]
Mula M, Hesdorffer DC, Trimble M, Sander JW. The role of titration schedule of topiramate for the development of depression in patients with epilepsy. Epilepsia 2009; 50(5): 1072-6.
[] [PMID: 19178563]
Rosenberg G. The mechanisms of action of valproate in neuropsychiatric disorders: Can we see the forest for the trees? Cell Mol Life Sci 2007; 64(16): 2090-103.
[] [PMID: 17514356]
69 Gabapentin Chadwick D. Recent advances in epilepsy. London: Churchill Livingstone 1992; pp. 211-22.
Errante LD, Petroff OA. Acute effects of gabapentin and pregabalin on rat forebrain cellular GABA, glutamate, and glutamine concentrations. Seizure 2003; 12(5): 300-6.
[] [PMID: 12810343]
Ryu JH, Lee PB, Kim JH, Do SH, Kim CS. Effects of pregabalin on the activity of glutamate transporter type 3. Br J Anaesth 2012; 109(2): 234-9.
[] [PMID: 22511482]
Cirrito JR, Yamada KA, Finn MB, et al. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron 2005; 48(6): 913-22.
[] [PMID: 16364896]
Wang Y, Ulland TK, Ulrich JD, et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med 2016; 213(5): 667-75.
[] [PMID: 27091843]
Yuan P, Condello C, Keene CD, et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 2016; 90(4): 724-39.
[] [PMID: 27196974]
Lee CYD, Daggett A, Gu X, et al. Elevated TREM2 gene dosage reprograms microglia responsivity and ameliorates pathological phenotypes in alzheimer's disease models. Neuron 2018; 97(5): 1032-48 e5.
Peters F, Salihoglu H, Pratsch K, et al. Tau deletion reduces plaque-associated BACE1 accumulation and decelerates plaque formation in a mouse model of Alzheimer’s disease. EMBO J 2019; 38(23): e102345.
[] [PMID: 31701556]

© 2022 Bentham Science Publishers | Privacy Policy