High-fat diet negatively affects brain markers, cognitive behaviors, and noncognitive behaviors in the rTg4510 tau mouse model.

Alzheimer's disease (AD) drastically impacts cognitive and noncognitive behaviors in both humans and animal models. Two hallmark proteins in AD, amyloid-ß plaques and tau neurofibrillary tangles, accumulate in regions of the brain critical for learning and memory, including the hippocampus. Poor dietary choices have been shown to exacerbate cognitive deficits seen in AD. In this study, we assessed the effects of a high-fat diet (HFD - 60 kcal% fat) on cognitive & noncognitive behaviors as well as on brain markers in the rTg4510 tau mouse model. While all mice learned the Morris Water Maze (MWM) task, it was noted that on the last day of acquisition female tau mice had a significantly higher latency to find the platform than male tau mice (p < 0.01). Mice given the HFD spent significantly less time in the target quadrant than those given a control diet (CD) (p < 0.05). Tau mice showed impaired burrowing (p < 0.05) and nesting behaviors (p < 0.001) compared to WT mice and HFD administration worsened burrowing in tau mice. Tau mice exhibited greater levels of glial fibrillary acidic protein (GFAP) (p < 0.05) and significantly less hippocampal cell density than WT mice (p < 0.001). We observed trends of HFD mice having greater levels of GFAP and greater average tangle size than CD mice. These results highlight the importance of dietary choices, especially in older populations more susceptible to AD and its effects.

White Button Mushroom (Agaricus bisporus) Supplementation Ameliorates Spatial Memory Deficits and Plaque Formation in an Amyloid Precursor Protein Mouse Model of Alzheimer's Disease.

Alzheimer's Disease (AD) is characterized by cognitive impairment and the presence of amyloid-ß (Aß) plaques and tau tangles. This study was conducted to assess the effects of white button mushroom (WBM) supplementation on spatial memory and plaque formation in mice with mutations in amyloid (Aß). Mice with amyloid precursor protein (hAPP) mutations and their wildtype (WT) littermates were fed a 10% white button mushroom (WBM) feed ad libitum three times per week, in addition to their normal diet. Morris water maze (MWM) was conducted at 14 and 32 weeks of age to assess spatial memory and Aß plaque pathology in the hippocampus was analyzed. Our results showed that hAPP mice on the WBM diet were faster in reaching the platform in the MWM compared to hAPP mice on the control diet at 32 weeks (p < 0.05). Significantly fewer plaque deposits were found in the hippocampi of hAPP mice on the WBM diet compared to those on the control diet at 32 weeks (p < 0.05). Overall, hAPP mice on the WBM diet had improved spatial memory at 32 weeks of age compared to those on the control diet and exhibited fewer amyloid plaques.

Lion's Mane (Hericium erinaceus) Exerts Anxiolytic Effects in the rTg4510 Tau Mouse Model.

Alzheimer's disease (AD) significantly impairs the life of an individual both cognitively and behaviorally. Tau and beta-amyloid (Aß) proteins are major contributors to the etiology of AD. This study used mice modeling AD through the presence of tau pathology to assess the effects of Hericium erinaceus (H. erinaceus), also known as Lion's mane, on cognitive and non-cognitive behaviors. Despite neurocognitive and neurobiological effects of H. erinaceus being seen in both healthy and transgenic mice, no research to date has explored its effects on mice with solely tau pathology. In this study, mice were placed on a diet supplemented with H. erinaceus or a standard rodent diet for 4.5 months in order to determine the effect of this medicinal mushroom on behavior. Tau mice given H. erinaceus had significantly shorter latencies to enter the center of the open field (OF) (p < 0.05) and spent significantly more time in the open arms of the elevated zero maze (EZM) (p < 0.001) compared to tau control mice. Mice given H. erinaceus spent significantly more time in the open arms of and made more head dips in the elevated zero maze (EZM) (p < 0.05). While H. erinaceus had anxiolytic effects, no improvements were seen in spatial memory or activities of daily living. These findings provide additional support for the anxiolytic effects of H. erinaceus and point to its potential benefit as a therapeutic for anxiety in AD.

Trace concentrations, heavy implications: Influences of biometals on major brain pathologies of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative condition that involves accumulation of toxic protein species, notably amyloid-ß (Aß)plaques and neurofibrillary tau tangles that are associated with cognitive decline. These proteins can bind metal ions, ultimately affecting their structure and function. In this review, we discuss key biometals such as zinc, copper, and iron that interact with protein species involved in AD, mainly Aß, tau, and the late-onset AD risk factor Apolipoprotein E (APOE). These metals interact with Aß and tau proteins, affecting their aggregation and toxicity. The allele variants of APOE also have different interactions with these metals, affecting APOE protein expression and aggregation of AD protein species.

Chronic Mild Unpredictable Stress and High-Fat Diet Given during Adolescence Impact Both Cognitive and Noncognitive Behaviors in Young Adult Mice.

Stress and diet are intricately linked, and they often interact in a negative fashion. Increases in stress can lead to poor food choices; adolescence is a period that is often accompanied by increased levels of stress. Stress and poor dietary choices can affect learning and memory; it is important to understand their combined effects when occurring during crucial developmental periods. Here, we present evidence that chronic mild unpredictable stress (CMUS) and high-fat diet (HFD) impact both cognitive and noncognitive behaviors when assessed after four weeks of manipulation in four-week old mice. CMUS mice had increased anxiety in the open field test (OFT) (p = 0.01) and spent more time in the open arms of the elevated zero maze (EZM) (p < 0.01). HFD administration was shown to interact with CMUS to impair spatial memory in the Morris Water Maze (MWM) (p < 0.05). Stress and diet also led to disturbances in non-cognitive behaviors: CMUS led to significantly more burrowing (p < 0.05) and HFD administration led to the poorer nest construction (p < 0.05). These findings allow for researchers to assess how modifying lifestyle factors (including diet and stress) during adolescence can serve as a potential strategy to improve cognition in young adulthood.

Wheel-Running Behavior Is Negatively Impacted by Zinc Administration in a Novel Dual Transgenic Mouse Model of AD.

Alzheimer's disease (AD) is a neurocognitive disorder that impacts both the brain and behavior. Metal ions, including zinc (Zn), have been seen to play an important role in AD-related pathology. In this study, we show alterations in wheel-running behavior both early and late in disease progression in a novel dual Tg mouse model of AD. This mouse includes both amyloid and tau pathology through its cross with the J20 (hAPP) and P301L (Tau) parentage. Animals were given either lab water or water that had been supplemented with 10 ppm Zn. Wheel running was assessed through individually housing mice and measuring wheel-running activity in both the light and dark cycles. Dual Tg mice showed significantly less activity in the first part of the dark cycle than WT mice at both 3.5 and 7 months of age (p < 0.05). Dual Tg mice given Zn water showed less activity compared to dual Tg mice on lab water, tau mice on Zn water, or WT mice given either lab or Zn water (p < 0.05) at 7 months. Female mice in this study consistently showed higher activity compared to male mice in all groups whereas Zn led to reduced activity. Daily activity rhythm was altered in both the tau and dual Tg mice, and Zn impacted this alteration through effects on amyloid, tau, and through circadian pathways.

Localization of Free and Bound Metal Species through X-Ray Synchrotron Fluorescence Microscopy in the Rodent Brain and Their Relation to Behavior.

Biometals in the brain, such as zinc, copper, and iron, are often discussed in cases of neurological disorders; however, these metals also have important regulatory functions and mediate cell signaling and plasticity. With the use of synchrotron X-ray fluorescence, our lab localized total, both bound and free, levels of zinc, copper, and iron in a cross section of one hemisphere of a rat brain, which also showed differing metal distributions in different regions within the hippocampus, the site in the brain known to be crucial for certain types of memory. This review discusses the several roles of these metals in brain regions with an emphasis on hippocampal cell signaling, based on spatial mapping obtained from X-ray fluorescence microscopy. We also discuss the localization of these metals and emphasize different cell types and receptors in regions with metal accumulation, as well as the potential relationship between this physiology and behavior.

A Novel hAPP/htau Mouse Model of Alzheimer's Disease: Inclusion of APP With Tau Exacerbates Behavioral Deficits and Zinc Administration Heightens Tangle Pathology.

The brains of those with Alzheimer's disease have amyloid and tau pathology; thus, mice modeling AD should have both markers. In this study, we characterize offspring from the cross of the J20 (hAPP) and rTg4510 (htau) strains (referred to as dual Tg). Behavior was assessed at both 3.5 and 7 months, and biochemical differences were assessed at 8 months. Additionally, mice were placed on zinc (Zn) water or standard lab water in order to determine the role of this essential biometal. Behavioral measures examined cognition, emotion, and aspects of daily living. Transgenic mice (dual Tg and htau) showed significant deficits in spatial memory in the Barnes Maze at both 3.5 and 7 months compared to controls. At 7 months, dual Tg mice performed significantly worse than htau mice (p < 0.01). Open field and elevated zero maze (EZM) data indicated that dual Tg and htau mice displayed behavioral disinhibition compared to control mice at both 3.5 and 7 months (p < 0.001). Transgenic mice showed significant deficits in activities of daily living, including burrowing and nesting, at both 3.5 and 7 months compared to control mice (p < 0.01). Dual Tg mice built very poor nests, indicating that non-cognitive tasks are also impacted by AD. Overall, dual Tg mice demonstrated behavioral deficits earlier than those shown by the htau mice. In the brain, dual Tg mice had significantly less free Zn compared to control mice in both the dentate gyrus and the CA3 of the hippocampus (p < 0.01). Dual Tg mice had increased tangles and plaques in the hippocampus compared to htau mice and the dual Tg mice given Zn water displayed increased tangle pathology in the hippocampus compared to htau mice on Zn water (p < 0.05). The dual Tg mouse described here displays pathology reminiscent of the human AD condition and is impaired early on in both cognitive and non-cognitive behaviors. This new mouse model allows researchers to assess how both amyloid and tau in combination impact behavior and brain pathology.