A longitudinal multimodal in vivo molecular imaging study of the 3xTg-AD mouse model shows progressive early hippocampal and taurine loss.

The understanding of the natural history of Alzheimer's disease (AD) and temporal trajectories of in vivo molecular mechanisms requires longitudinal approaches. A behavioral and multimodal imaging study was performed at 4/8/12 and 16 months of age in a triple transgenic mouse model of AD (3xTg-AD). Behavioral assessment included the open field and novel object recognition tests. Molecular characterization evaluated hippocampal levels of amyloid ß (Aß) and hyperphosphorylated tau. Magnetic resonance imaging (MRI) included assessment of hippocampal structural integrity, blood-brain barrier (BBB) permeability and neurospectroscopy to determine levels of the endogenous neuroprotector taurine. Longitudinal brain amyloid accumulation was assessed using 11C Pittsburgh compound B positron emission tomography (PET), and neuroinflammation/microglia activation was investigated using 11C-PK1195. We found altered locomotor activity at months 4/8 and 16 months and recognition memory impairment at all time points. Substantial early reduction of hippocampal volume started at month 4 and progressed over 8/12 and 16 months. Hippocampal taurine levels were significantly decreased in the hippocampus at months 4/8 and 16. No differences were found for amyloid and neuroinflammation with PET, and BBB was disrupted only at month 16. In summary, 3xTg-AD mice showed exploratory and recognition memory impairments, early hippocampal structural loss, increased Aß and hyperphosphorylated tau and decreased levels of taurine. In sum, the 3xTg-AD animal model mimics pathological and neurobehavioral features of AD, with early-onset recognition memory loss and MRI-documented hippocampal damage. The early-onset profile suggests temporal windows and opportunities for therapeutic intervention, targeting endogenous neuroprotectors such as taurine.

Retinal thinning of inner sub-layers is associated with cortical atrophy in a mouse model of Alzheimer's disease: a longitudinal multimodal in vivo study.

BACKGROUND: It has been claimed that the retina can be used as a window to study brain disorders. However, concerning Alzheimer's disease (AD), it still remains controversial whether changes occurring in the brain and retina are associated. We aim to understand when changes start appearing in the retina and brain, how changes progress, and if they are correlated. METHODS: We carried out a unique longitudinal study, at 4, 8, 12, and 16 months of age, in a triple transgenic mouse model of AD (3×Tg-AD), which mimics pathological and neurobehavioral features of AD, as we have already shown. Retinal structure and physiology were evaluated in vivo using optical coherence tomography and electroretinography. Brain visual cortex structure was evaluated in vivo using magnetic resonance imaging. RESULTS: The retinal thickness of 3×Tg-AD decreased, at all time points, except for the outer nuclear layer, where the opposite alteration was observed. Amplitudes in scotopic and photopic responses were increased throughout the study. Similarly, higher amplitude and lower phase values were observed in the photopic flicker response. No differences were found in the activity of retinal ganglion cells. Visual cortex gray matter volume was significantly reduced. CONCLUSIONS: Our results show that this animal model shows similar neural changes in the retina and brain visual cortex, i.e., retinal and brain thinning. Moreover, since similar changes occur in the retina and brain visual cortex, these observations support the possibility of using the eye as an additional tool (noninvasive) for early AD diagnosis and therapeutic monitoring.

The Retina as a Window or Mirror of the Brain Changes Detected in Alzheimer's Disease: Critical Aspects to Unravel.

Alzheimer's disease is the most frequent cause of dementia worldwide, representing a global health challenge, with a massive impact on the quality of life of Alzheimer's disease patients and their relatives. The diagnosis of Alzheimer's disease constitutes a real challenge, because the symptoms manifest years after the first degenerative changes occurring in the brain and the diagnosis is based on invasive and/or expensive techniques. Therefore, there is an urgent need to identify new reliable biomarkers to detect Alzheimer's disease at an early stage. Taking into account the evidence for visual deficits in Alzheimer's disease patients, sometimes even before the appearance of the first disease symptoms, and that the retina is an extension of the brain, the concept of the retina as a window to look into the brain or a mirror of the brain has received increasing interest in recent years. However, only a few studies have assessed the changes occurring in the retina and the brain at the same time points. Unlike previous reviews on this subject, which are mainly focused on brain changes, we organized this review by comprehensively summarizing findings related with structural, functional, cellular, and molecular parameters in the retina reported in both Alzheimer's disease patients and animal models. Moreover, we separated the studies that assessed only the retina, and those that assessed both the retina and brain, which are few but allow establishing correlations between the retina and brain. This review also highlights some inconsistent results in the literature as well as relevant missing gaps in this field.

Isolation of human umbilical arterial smooth muscle cells (HUASMC).

The human umbilical cord (UC) is a biological sample that can be easily obtained just after birth. This biological sample is, most of the time, discarded and their collection does not imply any added risk to the newborn or mother s health. Moreover no ethical concerns are raised. The UC is composed by one vein and two arteries from which both endothelial cells (ECs) and smooth muscle cells (SMCs), two of the main cellular components of blood vessels, can be isolated. In this project the SMCs were obtained after enzymatic treatment of the UC arteries accordingly the experimental procedure previously described by Jaffe et al. After cell isolation they were kept in t-flash with DMEM-F12 supplemented with 5% of fetal bovine serum and were cultured for several passages. Cells maintained their morphological and other phenotypic characteristics in the different generations. The aim of this study was to isolate smooth muscle cells in order to use them as models for future assays with constrictor drugs, isolate and structurally characterize L-type calcium channels, to study cellular and molecular aspects of the vascular function and to use them in tissue engineering.