Biomarkers.

Background: Tau phosphorylated at position 217 (pTau217) is considered to have the highest accuracy in identifying Alzheimer's disease (AD) pathology using blood. We describe a multi-cohort evaluation of the Simoa ALZpath pTau217 assay for the prediction of amyloid status in combination with additional blood-based AD biomarkers (GFAP, pTau181, etc.), as well as comparisons between histopathological and PET based amyloid measurements.

Biomarkers.

Background: Blood-based AD biomarker tests will be essential clinical tools to provide accessible and affordable screening and monitoring for AD disease-modifying therapeutics (DMT) as well as advancing overall clinical care. Tau phosphorylated at position 217 (pTau217) is considered to have the highest accuracy in identifying Alzheimer's disease (AD) pathology using blood. We describe a multi-cohort evaluation of the Simoa ALZpath pTau217 assay in plasma, including memory clinic patients, as well as performance in the context of other commercially available pTau217 assays.

Alzheimer's Imaging Consortium.

Background: Blood-based AD biomarker tests will be essential clinical tools to provide accessible and affordable screening and monitoring for AD disease-modifying therapeutics (DMT) as well as advancing overall clinical care. Tau phosphorylated at position 217 (pTau217) is considered to have the highest accuracy in identifying Alzheimer's disease (AD) pathology using blood. We describe a multi-cohort evaluation of the Simoa ALZpath pTau217 assay in plasma, including memory clinic patients, as well as performance in the context of other commercially available pTau217 assays.

The Iron Chelator Deferiprone Improves the Phenotype in a Mouse Model of Tauopathy.

Background: Abnormally hyperphosphorylated tau is a defining pathological feature of tauopathies, such as Alzheimer's disease (AD), and accumulating evidence suggests a role for iron in mediating tau pathology that may lead to cognitive decline in these conditions. The metal chelator deferiprone (DFP), which has a high affinity for iron, is currently in clinical trials for AD and Parkinson's disease. However, the effect of DFP on tau pathology remains underexplored.

Zinc Transporter-3 Knockout Mice Demonstrate Age-Dependent Alterations in the Metalloproteome.

Metals are critical cellular elements that are involved in a variety of cellular processes, with recent literature demonstrating that zinc, and the synaptic zinc transporter (ZnT3), are specifically involved in learning and memory and may also be key players in age-related neurodegenerative disorders such as Alzheimer's disease. Whilst the cellular content and location of metals is critical, recent data has demonstrated that the metalation state of proteins is a determinant of protein function and potential toxicity. As we have previously reported that ZnT3 knockout (KO) mice have deficits in total zinc levels at both 3 and 6 months of age, we were interested in whether there might be changes in the metalloproteomic profile in these animals.

Trehalose elevates brain zinc levels following controlled cortical impact in a mouse model of traumatic brain injury.

Zinc (Zn) deficiency is a clinical consequence of brain injury that can result in neuropathological outcomes that are exacerbated with age. Here, we present laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging data showing modulation of brain Zn levels by the disaccharide trehalose in aged mice following a controlled cortical impact model of traumatic brain injury. In this proof-of-concept study, trehalose induced an increase in brain zinc levels, providing important preliminary data for larger studies using this simple carbohydrate as a modulator of this essential micronutrient in traumatic brain injury.

Zinc Signal in Brain Diseases.

The divalent cation zinc is an integral requirement for optimal cellular processes, whereby it contributes to the function of over 300 enzymes, regulates intracellular signal transduction, and contributes to efficient synaptic transmission in the central nervous system. Given the critical role of zinc in a breadth of cellular processes, its cellular distribution and local tissue level concentrations remain tightly regulated via a series of proteins, primarily including zinc transporter and zinc import proteins. A loss of function of these regulatory pathways, or dietary alterations that result in a change in zinc homeostasis in the brain, can all lead to a myriad of pathological conditions with both acute and chronic effects on function.

Trehalose Improves Cognition in the Transgenic Tg2576 Mouse Model of Alzheimer's Disease.

This study assessed the therapeutic utility of the autophagy enhancing stable disaccharide trehalose in the Tg2576 transgenic mouse model of Alzheimer's disease (AD) via an oral gavage of a 2% trehalose solution for 31 days. Furthermore, as AD is a neurodegenerative condition in which the transition metals, iron, copper, and zinc, are understood to be intricately involved in the cellular cascades leading to the defining pathologies of the disease, we sought to determine any parallel impact of trehalose treatment on metal levels. Trehalose treatment significantly improved performance in the Morris water maze, consistent with enhanced learning and memory.

Trehalose improves traumatic brain injury-induced cognitive impairment.

Traumatic brain Injury (TBI) is a significant cause of death and long-term disability for which there are currently no effective pharmacological treatment options. In this study then, we utilized a mouse model of TBI to assess the therapeutic potential of the stable disaccharide trehalose, which is known to protect against oxidative stress, increase levels of chaperone molecules and enhance autophagy. Furthermore, trehalose has demonstrated neuroprotective properties in numerous animal models and has been proposed as a potential treatment for neurodegeneration.

Age modulates the injury-induced metallomic profile in the brain.

The biological transition metals iron (Fe), copper (Cu) and zinc (Zn) are thought to contribute to the neuronal pathologies that occur following traumatic brain injury (TBI), and indeed our previously published work in young (3 month-old) mice clearly demonstrates a significant spatiotemporal modulation of metals following TBI. Of note, however, is the literature observation that there is both an apparent detrimental effect of aging on TBI outcomes and an alteration in metals and their various transporters with normal advancing age. Therefore, to determine whether there was an interaction between aging, metals and TBI, we have utilised laser ablation-inductively coupled plasma-mass spectrometry to examine the spatial and temporal distribution of Fe, Zn and Cu following an acute controlled cortical impact brain injury in aged (24 months) rodents.

Laser ablation-inductively coupled plasma-mass spectrometry imaging of white and gray matter iron distribution in Alzheimer's disease frontal cortex.

Iron deposition in the brain is a feature of normal aging, though in several neurodegenerative disorders, including Alzheimer's disease, the rate of iron accumulation is more advanced than in age-matched controls. Using laser ablation-inductively coupled plasma-mass spectrometry imaging we present here a pilot study that quantitatively assessed the iron content of white and gray matter in paraffin-embedded sections from the frontal cortex of Alzheimer's and control subjects. Using the phosphorus image as a confirmed proxy for the white/gray matter boundary, we found that increased intrusion of iron into gray matter occurs in the Alzheimer's brain compared to controls, which may be indicative of either a loss of iron homeostasis in this vulnerable brain region, or provide evidence of increased inflammatory processes as a response to chronic neurodegeneration.

A time-course analysis of changes in cerebral metal levels following a controlled cortical impact.

Traumatic brain injury (TBI) is complicated by a sudden and dramatic change in brain metal levels, including iron (Fe), copper (Cu) and zinc (Zn). Specific 'metallo-pathological' features of TBI include increased non-heme bound Fe and the liberation of free Zn ions, both of which may contribute to the pathogenesis of TBI. To further characterise the metal dyshomeostasis that occurs following brain trauma, we performed a quantitative time-course survey of spatial Fe, Cu and Zn distribution in mice receiving a controlled cortical impact TBI.

Traumatic Brain Injury, Chronic Traumatic Encephalopathy, and Alzheimer's Disease: Common Pathologies Potentiated by Altered Zinc Homeostasis.

Alzheimer's disease, traumatic brain injury, and chronic traumatic encephalopathy represent conditions that have a profound socioeconomic impact for both the individual and the wider community. They are all characterized by specific protein aggregation that results in synaptic dysfunction, neuronal death, and consequent cognitive decline and memory loss. In this review, we present evidence to support the notion that the common pathologies found in all conditions, and indeed their associated cognitive deficits, may be linked by zinc (Zn²⁺) ion dyshomeostasis.