The locus coeruleus neurotoxin, DSP4, and/or a high sugar diet induce behavioral and biochemical alterations in wild-type mice consistent with Alzheimers related pathology
Alzheimer’s disease (AD) is the sixth leading cause of death in the United States where it is estimated that one in three seniors dies with AD or another dementia. Are modern lifestyle habits a contributing factor? Increased carbohydrate (sugar) consumption, stress and disruption of sleep patterns are quickly becoming the norm rather than the exception. Interestingly, seven months on a non-invasive high sucrose diet (20% sucrose in drinking water) has been shown to induce behavioral, metabolic and pathological changes consistent with AD in wild-type mice. As chronic stress and depression are associated with loss of locus coeruleus (LC) noradrenergic neurons and projections (source of anti-inflammatory and trophic factor control), we assessed the ability for a selective LC neurotoxin (DSP4) to accelerate and aggravate a high-sucrose mediated AD-related phenotype in wild-type mice. Male C57/Bl6 mice were divided into four groups: 1) saline injected, 2) DSP4 injected, 3) high sucrose drinking water (20%) or 4) DSP4 injected and high sucrose drinking water. We demonstrate that high sucrose consumption and DSP4 treatment promote an early-stage AD-related phenotype after only 3–4 months, as evidenced by elevated fecal corticosterone, increased despair, spatial memory deficits, increased AChE activity, elevated NO production, decreased pGSK3β and increased pTau. Combined treatment appears to accelerate and aggravate pathological processes consistent with Alzheimer disease and dementia. Developing a simple model in wild-type mice will highlight environmental and lifestyle factors that need to be addressed to slow, prevent or even reverse the rising trend in dementia patient numbers and cost.
KeywordsInsulin resistant brain state GSK3beta Phosphorylated Tau Locus coeruleus
This work was supported by the Saskatchewan Health Research Foundation (SHRF grant number 3075.
Compliance with ethical standards
None of the authors have any conflicts, financial or otherwise, to disclose. All authors approved the final manuscript.
- Debeir T, Marien M, Ferrario J, Rizk P, Prigent A, Colpaert F, Raisman-Vozari R (2004) In vivo upregulation of endogenous NGF in the rat brain by the alpha2-adrenoreceptor antagonist dexefaroxan: potential role in the protection of the basalocortical cholinergic system during neurodegeneration. Exp Neurol 190:384–395CrossRefPubMedGoogle Scholar
- Jardanhazi-Kurutz D, Kummer MP, Terwel D, Vogel K, Dyrks T, Thiele A, Heneka MT (2010) Induced LC degeneration in APP/PS1 transgenic mice accelerates early cerebral amyloidosis and cognitive deficits. Neurochem Int 57:375–382. https://doi.org/10.1016/j.neuint.2010.02.001 CrossRefPubMedGoogle Scholar
- Kalinin S, Gavrilyuk V, Polak PE, Vasser R, Zhao J, Heneka MT, Feinstein DL (2007) Noradrenaline deficiency in brain increases beta-amyloid plaque burden in an animal model of Alzheimer's disease. Neurobiol Aging 28:1206–1214. https://doi.org/10.1016/j.neurobiolaging.2006.06.003 CrossRefPubMedGoogle Scholar
- Lemos C, Rial D, Goncalves FQ et al (2016) High sucrose consumption induces memory impairment in rats associated with electrophysiological modifications but not with metabolic changes in the hippocampus. Neuroscience 315:196–205. https://doi.org/10.1016/j.neuroscience.2015.12.018 CrossRefPubMedGoogle Scholar
- Parr C, Mirzaei N, Christian M, Sastre M (2015) Activation of the Wnt/β-catenin pathway represses the transcription of the β-amyloid precursor protein cleaving enzyme (BACE1) via binding of T-cell factor-4 to BACE1 promoter. FASEB J 29:623–635. https://doi.org/10.1096/fj.14-253211 CrossRefPubMedGoogle Scholar
- Salkovic-Petrisic M, Hoyer S (2007) Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: an experimental approach. J Neural Transm Suppl:217–233Google Scholar
- Salkovic-Petrisic M, Osmanovic J, Grünblatt E, Riederer P, Hoyer S (2009) Modeling sporadic Alzheimer's disease: the insulin resistant brain state generates multiple long-term morphobiological abnormalities including hyperphosphorylated tau protein and amyloid-beta. J Alzheimers Dis 18:729–750. https://doi.org/10.3233/JAD-2009-1184 CrossRefPubMedGoogle Scholar
- Szot P, Franklin A, Miguelez C et al (2016) Depressive-like behavior observed with a minimal loss of locus coeruleus (LC) neurons following administration of 6-hydroxydopamine is associated with electrophysiological changes and reversed with precursors of norepinephrine. Neuropharmacology 101:76–86. https://doi.org/10.1016/j.neuropharm.2015.09.003 CrossRefPubMedGoogle Scholar