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

Abstract

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.

Examining the Role of the Noradrenergic Locus Coeruleus for Predicting Attention and Brain Maintenance in Healthy Old Age and Disease: An MRI Structural Study for the Alzheimer’s Disease Neuroimaging Initiative

“…Diet may also play a supportive role within the noradrenergic system as a preventing factor of neurodegenerative diseases. Indeed, poor and wrong diet-styles and their related neuroinflammatory consequences [ 171 , 172 , 173 ] are associated with worse prognosis and higher neurodegeneration risks [ 13 , 171 , 172 , 174 , 175 ]. Interventions on diet may be beneficial to restore potential harmful micro and macro nutrient insufficiencies according to current guidelines for prevention [ 13 , 176 ].…”

Dietary and metabolic risk of neuropsychiatric disorders: insights from animal models

“…The high-sugar diet is associated with an increased consumption of simple sugars, typically in the form of sucrose-or fructose-derived sweeteners. Several studies (81)(82)(83)(84)(85)(86)(87)(88)(89) have used a high-sugar diet (or 'high-sugar and high-fat' or 'Western diet') to intervene in rodents and observed the effects of anxiety/depression-like behaviour (also shown in Table 1). There is a study that has particularly attracted attention; male BALBc mice (an inbred immune-deficient mouse) were fed a high-sugar diet (60 % sugar) for 9 weeks, with a significant increase in body weight and total cholesterol, and the mice showed anxiety-like behaviour abnormalities.…”

Examining the Role of the Noradrenergic Locus Coeruleus for Predicting Attention and Brain Maintenance in Healthy Old Age, Mild Cognitive Impairment and Alzheimer’s Disease: An MRI Structural Study On the Adni Cohort

“…Diet may also play a supportive role within the noradrenergic system as a preventing factor of neurodegenerative diseases. Indeed, poor and wrong diet-styles and their related neuroinflammatory consequences [140,141,142] are associated with worse prognosis and higher neurodegeneration risks [13, 140, 141 143, 144]. Interventions on diet may be beneficial to restore potential harmful micro and macro nutrient insufficiencies according to current guidelines for prevention [145].…”