Effect of Subchronic Treatment of Memantine, Galantamine, and Nicotine in the Brain of Tg2576 (APPswe) Transgenic Mice

Unger, Christina; Svedberg, Marie; Yu, Wenbin; Hedberg, Monika M.; Nordberg, Agneta

doi:10.1124/jpet.105.098566

Cited by 57 publications

(47 citation statements)

References 37 publications

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“…Our results are consistent with previous studies which found decreases in cortical APP levels in Tg2576 mice after 10 days of memantine treatment (Unger et al, 2006). However, the mechanism by which memantine regulates amyloid metabolism is not clear.…”

Section: Discussionsupporting

confidence: 83%

Effects of Memantine on Neuronal Structure and Conditioned Fear in the Tg2576 Mouse Model of Alzheimer's Disease

Dong

Yuede

Coughlan

et al. 2008

Neuropsychopharmacol

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Memantine, an uncompetitive NMDA receptor antagonist used for the treatment of Alzheimer's disease (AD), has been hypothesized to have neuroprotective properties. However, the similarity of its mechanism of action to other NMDA receptor antagonists has led to concerns that it may also have neurotoxic effects. To assess both the neuroprotective and neurotoxic potential of memantine in a mouse model of AD (Tg2576 mice), we used quantitative light and electron microscopy to investigate the effects of long-term (6 months) administration of memantine (5, 10 and 20 mg/kg) on plaque deposition and neuronal morphology in the hippocampus and overlying cortex. A fear-conditioning paradigm was used to evaluate the behavioral consequences of any observed changes in structure. Administration of the two higher doses of memantine (10 and 20 mg/kg) was associated with a significant decrease in b-amyloid (Ab) plaque deposition, increases in synaptic density and the appearance of degenerating axons; the latter two effects were independent of genotype. Administration of the lowest dose of memantine (5 mg/kg) was associated with a significant decrease in Ab plaque deposition and a significant increase in synaptic density, but not a significant increase in degenerating axons. However, memantine did not significantly improve behavioral deficits associated with genotype in a fear-conditioning paradigm at any dose. These results suggest that chronic memantine administration may have both neuroprotective and neurotoxic effects in a mouse model of AD.

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Section: Discussionsupporting

confidence: 83%

Effects of Memantine on Neuronal Structure and Conditioned Fear in the Tg2576 Mouse Model of Alzheimer's Disease

Dong

Yuede

Coughlan

et al. 2008

Neuropsychopharmacol

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“…Saxena et al (2011) have shown that a 14-day chronic Nic treatment in icv-STZ-treated animals avoids mitochondrial dysfunctions and caspase-3 activity, evidencing the Nic protective influence against apoptosisrelated processes. Our findings, together with those from Srivareerat et al (2011), are in agreement with multiple reports on Nic neuroprotective roles (Fujii and Sumikawa, 2001;Picciotto and Zoli, 2002;Liu and Zhao, 2004;Unger et al, 2006;Poorthuis et al, 2009). In addition, it has been shown that neuroprotection is blocked by nAChR antagonists (Akaike et al, 2010), and that nicotinic receptors can modulate mnemonic processes involving ACh release and Ca 2+ homeostasis (Se´gue´la et al, 1993;McGehee et al, 1995).…”

Section: Discussionsupporting

confidence: 83%

Chronic nicotine attenuates behavioral and synaptic plasticity impairments in a streptozotocin model of Alzheimer’s disease

et al. 2017

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Abstract-Brain glucose metabolism is altered in sporadic Alzheimer's disease (sAD), whose pathologies are reproduced in rodents by intracerebroventricular (icv) infusion of streptozotocin (STZ) in subdiabetogenic doses. The icv-STZ model also culminates in central cholinergic dysfunctions, which in turn are known to underlie both the sAD cognitive decline, and synaptic plasticity impairments. Considering the cognitive-enhancing potential of chronic nicotine (Nic), we investigated whether it attenuates icv-STZ-induced impairments in recognition memory and synaptic plasticity in a cognition-relevant substrate: the hippocampal CA1-medial prefrontal cortex (mPFC) pathway. Rats treated with icv-STZ were submitted to a chronic Nic regime, and were evaluated for recognition memory. We then examined long-term potentiation (LTP), paired-pulse facilitation (PPF) under urethane anesthesia, and brains were also evaluated for hippocampus-mPFC cell density. We found that Nic treatment prevents icv-STZ-induced disruptions in recognition memory and LTP. STZ did not precipitate neuronal death, while Nic alone was associated with higher neuronal density in CA1 when compared to vehicle-injected animals. Through combining behavioral, neurophysiological, and neuropathological observations into the Nic-STZ interplay, our study reinforces that cholinergic treatments are of clinical importance against earlystage Alzheimer's disease and mild cognitive impairments.

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“…In contrast to earlier studies [22,35] , we did not observe any significant changes in synaptophysin levels in the APPswe mice compared with nontransgenic controls. A possible explanation might be the use of another mouse genetic background strain (C6/SJL) compared with C57B6 in the previous studies.…”

Section: Discussioncontrasting

confidence: 56%

Effect of Huprine X on β-Amyloid, Synaptophysin and α7 Neuronal Nicotinic Acetylcholine Receptors in the Brain of 3xTg-AD and APPswe Transgenic Mice

et al. 2010

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Background: Several studies implicate acetylcholinesterase (AChE) in the pathogenesis of Alzheimer’s disease (AD), raising the question of whether inhibitors of AChE also might act in a disease-modifying manner. Huprine X (HX), a reversible AChE inhibitor hybrid of tacrine and huperzine A, has shown to affect the amyloidogenic process in vitro. In this study, the aim was to investigate whether HX could affect the AD-related neuropathology in vivoin two mouse models. Methods:Tg2576 (K670M/N671L) (APPswe) and 3xTg-AD (K670M/N671L, PS1M146V, tauP301L) mice were treated with HX (0.12 µmol/kg, i.p., 21 days) or saline at 6–7 months. Human β-amyloid (Aβ) was measured by ELISA, synaptophysin by Western blot and α7 neuronal nicotinic acetylcholine receptors (nAChRs) were analyzed by [¹²⁵I]α-bungarotoxin autoradiography. Results: Treatment with HX reduced insoluble Aβ1–40 (about 40%) in the hippocampus of 3xTg-AD mice, while showing no effect in APPswe mice. Additionally, HX markedly increased cortical synaptophysin levels (about 140%) and decreased (about 30%) the levels of α7 nAChRs in the caudate nucleus of 3xTg-AD mice, while increasing (about 10%) hippocampal α7 nAChRs in APPswe mice. Conclusion: The two mouse models react differently to HX treatment, possibly due to their differences in brain neuropathology. The modulation of Aβ and synaptophysin by HX in 3xTg-AD mice might be due to its suggested interaction with the peripheral anionic site on AChE, and/or via cholinergic mechanisms involving activation of cholinergic receptors. Our results provide further evidence that drugs targeting AChE affect some of the fundamental processes that contribute to neurodegeneration, but whether HX might act in a disease-modifying manner in AD patients remains to be proven.

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Effect of Subchronic Treatment of Memantine, Galantamine, and Nicotine in the Brain of Tg2576 (APPswe) Transgenic Mice

Cited by 57 publications

References 37 publications

Effects of Memantine on Neuronal Structure and Conditioned Fear in the Tg2576 Mouse Model of Alzheimer's Disease

Effects of Memantine on Neuronal Structure and Conditioned Fear in the Tg2576 Mouse Model of Alzheimer's Disease

Chronic nicotine attenuates behavioral and synaptic plasticity impairments in a streptozotocin model of Alzheimer’s disease

Effect of Huprine X on β-Amyloid, Synaptophysin and α7 Neuronal Nicotinic Acetylcholine Receptors in the Brain of 3xTg-AD and APPswe Transgenic Mice

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