Inflammatory processes are a hallmark of many chronic diseases including Alzheimer's disease and diabetes mellitus. Fairly recent statistical evidence indicating that type 2 diabetes increases the risk of developing Alzheimer's disease has led to investigations of the potential common processes that could explain this relation. Here, we review the literature on how inflammation and the inducible nuclear factor NF-kappaB might be involved in both diabetes mellitus and Alzheimer's disease and whether these factors can link both diseases.

Previous studies have shown that tumor necrosis factor‐alpha (TNF‐α) induces neuroprotection against excitotoxic damage in primary cortical neurons via sustained nuclear factor‐kappa B (NF‐κB) activation. The transcription factor NF‐κB can regulate the expression of small conductance calcium‐activated potassium (KCa) channels. These channels reduce neuronal excitability and as such may yield neuroprotection against neuronal overstimulation. In the present study we investigated whether TNF‐α‐mediated neuroprotective signaling is inducing changes in the expression of small conductance KCa channels. Interestingly, the expression of KCa2.2 channel was up‐regulated by TNF‐α treatment in a time‐dependent manner whereas the expression of KCa2.1 and KCa2.3 channels was not altered. The increase in KCa2.2 channel expression after TNF‐α treatment was shown to be dependent on TNF‐R2 and NF‐κB activation. Furthermore, activation of small conductance KCa channels by 6,7‐dichloro‐1H‐indole‐2,3‐dione 3‐oxime or cyclohexyl‐[2‐(3,5‐dimethyl‐pyrazol‐1‐yl)‐6‐methyl‐pyrimidin‐4‐yl]‐amine‐induced neuroprotection against a glutamate challenge. Treatment with the small conductance KCa channel blocker apamin or KCa2.2 channel siRNA reverted the neuroprotective effect elicited by TNF‐α. We conclude that treatment of primary cortical neurons with TNF‐α leads to increased KCa2.2 channel expression which renders neurons more resistant to excitotoxic cell death.

The dysfunction and loss of basal forebrain cholinergic neurons and their cortical projections are among the earliest pathological events in the pathogenesis of Alzheimer's disease (AD). The evidence pointing to cholinergic impairments come from studies that report a decline in the activity of choline acetyltransferase (ChAT) and acetylcholine esterase (AChE), acetylcholine (ACh) release and the levels of nicotinic and muscarinic receptors, and loss of cholinergic basal forebrain neurons in the AD brain. Alzheimer's disease pathology is characterized by an extensive loss of synapses and neuritic branchings which are the dominant scenario as compared to the loss of the neuronal cell bodies themselves. The appearance of cholinergic neuritic dystrophy, i.e. aberrant fibers and fiber swelling are more and more pronounced during brain aging and widely common in AD. When taking amyloid-β (Aβ) deposition as the ultimate causal factor of Alzheimer's disease the role of Aβ in cholinergic dysfunction should be considered. In that respect it has been stated that ACh release and synthesis are depressed, axonal transport is inhibited, and that ACh degradation is affected in the presence of Aβ peptides. β-Amyloid peptide 1-42, the principal constituent of the neuritic plaques seen in AD patients, is known to trigger excess amount of glutamate in the synaptic cleft by inhibiting the astroglial glutamate transporter and to increase the intracellular Ca(2+) level. Based on the glutamatergic overexcitation theory of AD progression, the function of NMDA receptors and treatment with NMDA antagonists underlie some recent therapeutic applications. Memantine, a moderate affinity uncompetitive NMDA receptor antagonist interacts with its target only during states of pathological activation but does not interfere with the physiological receptor functions. In this study the neuroprotective effect of memantine on the forebrain cholinergic neurons against Aβ42 oligomers-induced toxicity was studied in an in vivo rat dementia model. We found that memantine rescued the neocortical cholinergic fibers originating from the basal forebrain cholinergic neurons, attenuated microglial activation around the intracerebral lesion sides, and improved attention and memory of Aβ42-injected rats exhibiting impaired learning and loss of cholinergic innervation of neocortex.

Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Granic, I., Nyakas, C., Luiten, P. G. M., Eisel, U. L. M., Halmy, L. G., Gross, G., ... Nimmrich, V. (2010). Calpain inhibition prevents amyloid-beta-induced neurodegeneration and associated behavioral dysfunction in rats. Neuropharmacology, 59(4-5), 334-342. DOI: 10.1016334-342. DOI: 10. /j.neuropharm.2010 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. s t r a c tAmyloid-b (Ab) is toxic to neurons and such toxicity is e at least in part e mediated via the NMDA receptor. Calpain, a calcium dependent cystein protease, is part of the NMDA receptor-induced neurodegeneration pathway, and we previously reported that inhibition of calpain prevents excitotoxic lesions of the cholinergic nucleus basalis magnocellularis of Meynert. The present study reveals that inhibition of calpain is also neuroprotective in an in vivo model of Ab oligomer-induced neurodegeneration in rats. Ab-induced lesions of the nucleus basalis induced a significant decrease in the number of cholinergic neurons and their projecting fibers, as determined by analysis of choline-acetyltransferase in the nucleus basalis magnocellularis and cortical mantle of the lesioned animals. Treatment with the calpain inhibitor A-705253 significantly attenuated cholinergic neurodegeneration in a dose-dependent manner. Calpain inhibition also significantly diminished the accompanying neuroinflammatory response, as determined by immunohistochemical analysis of microglia activation. Administration of b-amyloid markedly impaired performance in the novel object recognition test. Treatment with the calpain inhibitor, A-705253, dose-dependently prevented this behavioral deficit.In order to determine whether pre-treatment with the calpain inhibitor is necessary to exhibit its full protective effect on neurons we induced Ab toxicity in primary neuronal cultures and administered A-705253 at various time points before and after Ab oligomer application. Although the protective effect was higher when A-705253 was applied before induction of Ab toxicity, calpain inhibition was still beneficial when applied up to 1 h post-treatment.We conclude that inhibition of calpains may represent a valuable strategy for the prevention of Ab oligomer-induced neuronal decline and associated cognitive deterioration.