Deposition of amyloid beta protein (Aβ) is a key component in the pathogenesis of Alzheimer's disease (AD). As an anti-amyloid natural polyphenol, curcumin (Cur) has been used as a therapy for AD. Its fluorescent activity, preferential binding to Aβ, as well as structural similarities with other traditional amyloid-binding dyes, make it a promising candidate for labeling and imaging of Aβ plaques in vivo. The present study was designed to test whether dietary Cur and nanocurcumin (NC) provide more sensitivity for labeling and imaging of Aβ plaques in brain tissues from the 5×-familial AD (5×FAD) mice than the classical Aβ-binding dyes, such as Congo red and Thioflavin-S. These comparisons were made in postmortem brain tissues from the 5×FAD mice. We observed that Cur and NC labeled Aβ plaques to the same degree as Aβ-specific antibody and to a greater extent than those of the classical amyloid-binding dyes. Cur and NC also labeled Aβ plaques in 5×FAD brain tissues when injected intraperitoneally. Nanomolar concentrations of Cur or NC are sufficient for labeling and imaging of Aβ plaques in 5×FAD brain tissue. Cur and NC also labeled different types of Aβ plaques, including core, neuritic, diffuse, and burned-out, to a greater degree than other amyloid-binding dyes. Therefore, Cur and or NC can be used as an alternative to Aβ-specific antibody for labeling and imaging of Aβ plaques ex vivo and in vivo. It can provide an easy and inexpensive means of detecting Aβ-plaque load in postmortem brain tissue of animal models of AD after anti-amyloid therapy.

Neurodegenerative diseases are an enormous public health problem, affecting tens of millions of people worldwide. Nearly all of these diseases are characterized by oligomerization and fibrillization of neuronal proteins, and there is great interest in therapeutic targeting of these aggregates. Here, we show that soluble aggregates of α-synuclein and tau bind to plateimmobilized PrP in vitro and on mouse cortical neurons, and that this binding requires at least one of the same N-terminal sites at which soluble Aβ aggregates bind. Moreover, soluble aggregates of tau, α-synuclein and Aβ cause both functional (impairment of LTP) and structural (neuritic dystrophy) compromise and these deficits are absent when PrP is ablated, knocked-down, or when neurons are pre-treated with anti-PrP blocking antibodies. Using an all-human experimental paradigm involving: (1) isogenic iPSC-derived neurons expressing or lacking PRNP, and (2) aqueous extracts from brains of individuals who died with Alzheimer's disease, dementia with Lewy bodies, and Pick's disease, we demonstrate that Aβ, α-synuclein and tau are toxic to neurons in a manner that requires PrP C. These results indicate that PrP is likely to play an important role in a variety of late-life neurodegenerative diseases and that therapeutic targeting of PrP, rather than individual disease proteins, may have more benefit for conditions which involve the aggregation of more than one protein.

Recent clinical and epidemiological studies support the contention that diabetes mellitus (DM) is a strong risk factor for the development of Alzheimer’s disease (AD). The use of insulin cell toxin, streptozotocin (STZ), when injected into the lateral ventricles, develops an insulin resistant brain state (IRBS) and represents a non-transgenic, or sporadic AD model (SAD), with several AD-like neuropathological features. The present study explored the effects of an anti-diabetic drug, liraglutide (LIR), in reversing major pathological hallmarks in the prodromal disease stage of both the 5xFAD transgenic and SAD mouse models of AD. Three-month-old 5xFAD and age-matched wild type mice were given a single intracerebroventricular (i.c.v) injection of STZ or vehicle (saline) and were subsequently treated with LIR, intraperitoneally (IP), once a day for 30 days. The extent of neurodegeneration, Aβ plaque load, and key proteins associated with the insulin signaling pathways were measured using Western blot and neuroinflammation (via immunohistological assays) in the cortical and hippocampal regions of the brain were assessed following a series of behavioral tests used to measure cognitive function after LIR or vehicle treatments. Our results indicated that STZ significantly increased neuroinflammation, Aβ plaque deposition and disrupted insulin signaling pathway, while 25 nmol/kg LIR, when injected IP, significantly decreased neuroinflammatory responses in both SAD and 5xFAD mice before significant cognitive changes were observed, suggesting LIR can reduce early neuropathology markers prior to the emergence of overt memory deficits. Our results indicate that LIR has neuroprotective effects and has the potential to serve as an anti-inflammatory and anti-amyloid prophylactic therapy in the prodromal stages of AD.

In cerebral ischemia, studies of cell death have focused primarily on neurons, but recent work indicates that ischemia also causes damage to astrocytes. Activation of astrocytes is a typical brain response to stress stimuli and is evidenced by changes in cellular function and morphology, as well as upregulation of glial fibrillary acidic protein. The tumor-suppressor transcription factor p53 has recently been implicated as a mediator of ischemia-induced neuronal death, but very little is known about its role in the activation or the death of astrocytes. The present study investigated the role of p53 in astrocyte and neuronal toxicity using in-vitro and in-vivo ischemic stroke models. We showed that p53 is activated in ischemic brains and in oxygen-glucose deprivation (OGD)-induced cell death in neurons and astrocytes. Inhibition of p53 activity using either pifithrin-α or small interference RNA interference reduced OGD-induced cell death and pifithrin-α reversed OGD-induced impairment of glutamate uptake in astrocytes, suggesting that p53 might play a key role in mediating neurotoxicity and gliotoxicity in ischemic brain injury. This study shows that p53 is activated in astrocytes during ischemia and that inhibition of the activity of this molecule prevents not only OGD-induced neuronal and astrocytic death but also astrocyte activation and impaired glutamate uptake. These findings suggest that p53 may be a valuable therapeutic target in ischemic brain injury.

AD patients and, by impairing vessel-mediated clearance of amyloidbeta, may accelerate disease development. We have shown that neutrophils plug blood flow in a small fraction of brain capillaries and that blocking this adhesion substantially increases brain blood flow in mouse models of AD. Therapies that interfered with this capillary plugging could complement those aimed at reducing amyloid. Background: Alzheimer's disease (AD) is an intricate protein misfolding neurodegenerative disorder, largely characterized by the misfolding and seeding of amyloid beta (Ab) and tau proteins. There are a myriad of risk factors associated with developing AD, with age being the number one factor. Although this is true, gender is also a risk factor of concern with the proportion of women-to-men diagnosed with AD skewed, with women being diagnosed significantly more than men. Heat shock protein 70 (HSP70) has the ability to bind to misfolded proteins and either tag them for the ubiquitin/lysosomal pathway or refold them into the correct structural configuration. Myocardial research has indicated gender bias in HSP70 expression, with men showing higher HSP70 expression. It is hypothesized that an interaction between 17-beta estradiol (E2), estrogen receptor-a (ER-a) and HSP90 is causing a decrease in HSP70 translation. The premise behind this study was to examine this relationship, in addition to behavior, at early time-points of disease progression in a neurodegenerative transgenic mouse model of AD. Methods: Male and female 5xFAD transgenic mice at the ages of 1, 2 and 4 months of age underwent a series of behavioral assays to assess motoric and cognitive abilities, including open field, novel object recognition, and passive avoidance. At the end of the study, immunohistology and Western blot analysis were conducted to determine protein expression of HSP70, 90, ER-a, and Ab. An ELISA was conducted to analyze plasma estrogen levels (E2). Results: Preliminary results indicate that there is a gender-specific difference in performance in the passive avoidance task, AD females have a significantly shorter latency compared to their AD male littermates. Preliminary results also indicate differences in various protein expression levels in Western blot analysis. Conclusions: A gender difference exists in 5xFAD mice, but more research is warranted to further analyze this difference.

BackgroundCognitively complex everyday tasks may be affected in early stages of Alzheimer’s disease. Performance‐based digital assessments could facilitate more precise measurement of subtle changes in everyday functioning. We piloted a novel smartphone app ‘Assessment of Smartphone Everyday Tasks’ (ASSET), to investigate its utility for measuring everyday functioning in cognitively normal older adults. ASSET consists of Patient Portal and Calendar tasks for renewing prescriptions, making payments, and scheduling urgent and recurring appointments (Figure1). It tracks response time and accuracy.MethodASSET was piloted in 34 participants (n = 20 cognitively normal young adults (YN): 21.3±2.6 years, 85%female, median 14.5 years of education; n = 14 cognitively normal older adults (ON), 75.1±4.8 years, 71%female, median 18 years of education). At baseline, participants completed the first version of ASSET and the Preclinical Alzheimer’s Cognitive Composite (PACC5) in the research clinic. ON participants and their study partners completed the Alzheimer’s Disease Cooperative Study Activities of Daily Living – Prevention Instrument (ADCS ADL‐PI). We calculated accuracy rates (correct responses/task duration) for both tasks and computed Pearson’s r correlation coefficients between subtasks (internal consistency) and with PACC5 and ADCS ADL‐PI (construct validity). To investigate test‐retest reliability, participants subsequently completed the first and five alternate versions of ASSET remotely on a fixed, biweekly schedule.ResultAt baseline, the Patient Portal and Calendar tasks were highly correlated (r = 0.78, 95% confidence interval (95%CI) = [0.60,0.89]). YN performed better on both tasks than ON, completing them faster and making fewer errors (Patient Portal: Cohen’s d = ‐3.0, 95%CI = [‐4.2, ‐1.8]; Calendar: d = ‐1.6, 95%CI = [‐2.4, ‐0.7]). Performance was moderately correlated with PACC5 (Patient Portal: r = 0.59, 95%CI = [0.49,0.67]; Calendar: r = 0.48, 95%CI = [0.37,0.58]). Among ON, performance on ASSET was not significantly correlated with either self‐ or study partner‐reported ADCS ADL‐PI. Over repeated assessments, Patient Portal accuracy increased, while Calendar accuracy increased but dropped at the last assessment among all participants (see Figure2).ConclusionInitial results show that ASSET may have good internal consistency and good ability to distinguish young from older cognitively normal adults. Future research should aim to corroborate current findings and extend with Alzheimer’s disease biomarkers to better understand the value of ASSET in detecting early changes in everyday functioning.