Chronic Memantine Treatment Ameliorates Behavioral Deficits, Neuron Loss, and Impaired Neurogenesis in a Model of Alzheimer’s Disease

Abstract

Memantine, a non-competitive NMDA receptor antagonist possessing neuroprotective properties, belongs to the small group of drugs which have been approved for the treatment of Alzheimer’s disease (AD). While several preclinical studies employing different transgenic AD mouse models have described beneficial effects with regard to rescued behavioral deficits or reduced amyloid plaque pathology, it is largely unknown whether memantine might have beneficial effects on neurodegeneration. In the current study, we assessed whether memantine treatment has an impact on hippocampal neuron loss and associated behavioral deficits in the Tg4-42 mouse model of AD. We demonstrate that a chronic oral memantine treatment for 4 months diminishes hippocampal CA1 neuron loss and rescues learning and memory performance in different behavioral paradigms, such as Morris water maze or a novel object recognition task. Cognitive benefits of chronic memantine treatment were accompanied by an amelioration of impaired adult hippocampal neurogenesis. Taken together, our results demonstrate that memantine successfully counteracts pathological alterations in a preclinical mouse model of AD.

Memantine ameliorates cognitive deficit in AD mice via enhancement of entorhinal–CA1 projection

“…Treatment of AD with memantine reduce the amount of insoluble Aβ partly through NMDA receptors and then restore the glutamate homeostasis in animal models of AD [ 42 – 44 ]. Chronic oral memantine treatment can reduces hippocampal CA1 neuron loss and restore learning and memory performance [ 37 ]. Our research results also confirm that memantine improves cognitive behaviors in AD mice, which is consistent with previous reports.…”

Characterization of a Mouse Model of Alzheimer’s Disease Expressing Aβ4-42 and Human Mutant Tau

“…On both days, exploration time of each object was recorded manually for every mouse during the single 5 min trial sessions. The recognition performances was quantified using the Discrimination Index (DI), measured as the differences between novel (T novel ) and familiar (T familiar ) object exploration times in proportion to the animal’s total exploration time (T total ) [ 25 ].…”

“…Neuron loss was assessed in the CA1 region of the hippocampus on sagittal brain sections (bregma 0.72–1.08) of 3- and 5-month-old mice (n = 6–7 per time point) as previously described [ 25 ]. Paraffin sections of 4 µm thickness (3 sections per animal, at least 30 μm apart) were stained with hematoxylin to identify the nuclei.…”

“…Aβ 4–42 peptides are among the first Aβ peptides that have been identified in human AD brain and represent a highly abundant peptide species [ 1 , 22 , 23 ]. Tg4–42 mice do not form overt extracellular Aβ deposits but present robust behavioral deficits together with abundant CA1 neuron loss at an age of 6 months [ 24 , 25 ].…”

Postconditioning with Sevoflurane or Propofol Alleviate Lipopolysaccharide-Induced Neuroinflammation, but Exert Dissimilar Effects on NR2B Subunit and Cognition

“…The non-competitive antagonist memantine which selectively inhibits the extrasynaptic NMDARs at a low dose was administered i.p. for 7 consecutive days after postconditioning with propofol as previously described [28,50]. An equal volume of saline was administered in sham rats (Fig.…”