Age-associated pathophysiological changes such as neurodegenerative diseases are multifactorial conditions with increasing incidence and no existing cure. The possibility of altering the progression and development of these multifactorial diseases through diet is an attractive approach with increasing supporting data. Epidemiological and clinical studies have highlighted the health potential of diets rich in fruits and vegetables. Such food sources are rich in (poly)­phenols, natural compounds increasingly associated with health benefits, having the potential to prevent or retard the development of various diseases. However, absorption and the blood concentration of (poly)­phenols is very low when compared with their corresponding (poly)­phenolic metabolites. Therefore, these serum-bioavailable metabolites are much more promising candidates to overcome cellular barriers and reach target tissues, such as the brain. Bearing this in mind, it will be reviewed that the molecular mechanisms underlying (poly)­phenolic metabolites effects, range from 0.1 to <50 μM and their role on neuroinflammation, a central hallmark in neurodegenerative diseases.

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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 (A ) 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 11 C Pittsburgh compound B positron emission tomography (PET), and neuroinflammation/microglia activation was investigated using 11 C-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 A 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.

The world of (poly)phenols arising from dietary sources has been significantly amplified with the discovery of low molecular weight (LMW) (poly)phenol metabolites resulting from phase I and phase II metabolism and microbiota transformations. These metabolites, which are known to reach human circulation have been studied to further explore their interesting properties, especially regarding neuroprotection. Nevertheless, once in circulation, their distribution to target tissues, such as the brain, relies on their ability to cross the blood-brain barrier (BBB), one of the most controlled barriers present in humans. This represents a key step of an underexplored journey towards the brain. Present review highlights the main findings related to the ability of LMW (poly)phenol metabolites to reach the brain, considering different studies: in silico, in vitro, and in vivo. The mechanisms associated with the transport of these LMW (poly)phenol metabolites across the BBB and possible transporters will be discussed. Overall, the transport of these LMW (poly)phenol metabolites is crucial to elucidate which compounds may exert direct neuroprotective effects, so it is imperative to continue dissecting their potential to cross the BBB and the mechanisms behind their permeation.

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Scope: Diets rich in (poly)phenols have been associated with positive effects on neurodegenerative disorders, such as Parkinson's disease (PD). Several low-molecular weight (poly)phenol metabolites (LMWPM) are found in the plasma after consumption of (poly)phenol-rich food. It is expected that LMWPM, upon reaching the brain, may have beneficial effects against both oxidative stress and neuroinflammation, and possibly attenuate cell death mechanisms relate to the loss of dopaminergic neurons in PD. Methods and Results: This study investigates the neuroprotective potential of two blood-brain barrier permeant LMWPM, catechol-O-sulfate (cat-sulf ), and pyrogallol-O-sulfate (pyr-sulf ), in a human 3D cell model of PD. Neurospheroids were generated from LUHMES neuronal precursor cells and challenged by 1-methyl-4-phenylpyridinium (MPP + ) to induce neuronal stress. LMWPM pretreatments were differently neuroprotective towards MPP + insult, presenting distinct effects on the neuronal transcriptome. Particularly, cat-sulf pretreatment appeared to boost counter-regulatory defense mechanisms (preconditioning). When MPP + is applied, both LMWPM positively modulated glutathione metabolism and heat-shock response, as also favorably shifting the balance of pro/anti-apoptotic proteins. Conclusions: Our findings point to the potential of LMWPM to trigger molecular mechanisms that help dopaminergic neurons to cope with a subsequent toxic insult. They are promising molecules to be further explored in the context of preventing and attenuating parkinsonian neurodegeneration.

Purpose The diagnosis of Alzheimer's disease (AD) is difficult. Since AD patients have visual problems, even before AD diagnosis, and retina is part of the CNS, we aim to understand whether retina could be used as a window to the brain, and for earlier and better diagnosis of AD. Methods To achieve this, we are performing a longitudinal study to evaluate potential changes in several molecular, cellular, structural and physiological parameters in the retina of a triple transgenic mouse model (3xTg‐AD), comparing to age‐matched wild‐type (C57BL6/129S) mice, at 4, 8 and 12 months (M) of age, by Western blot, immunohistochemistry, TUNEL assay, ERG, PERG and OCT. Results In 3xTg‐AD mice, at 8 and 12 M, the retinal thickness decreased significantly, and at 4, 8 and 12 M the scotopic b‐wave and photopic flicker amplitude increased. No differences were detected in PERG recordings. Amyloid beta protein was not detected in the retina of 3xTg‐AD at 4 and 8 M. The p‐Tau protein levels increased at 4 M, but not at 8 M. At 4 and 8 M, amyloid precursor protein, beta‐secretase 1, choline acetyltransferase, syntaxin and synaptophysin levels remained unchanged in the retina of 3xTg‐AD. Apoptotic cells (TUNEL+ cells) were not detected. Also, no alterations were detected in the immunostaining of vimentin in 3xTg‐AD, but GFAP immunostaining decreased at 8 M. Conclusions These results show that retinal thickness and function are early affected in a mouse model of AD. However, no molecular and cellular correlates were found in the majority of parameters evaluated in the retina, with the exception of p‐Tau and GFAP, at least in early timepoints. Support: Santa Casa Mantero Belard Award 2015 (MB‐1049‐2015); FCT Portugal, PEst (UID/NEU/04539/2013), COMPETE‐FEDER (POCI‐01‐0145‐FEDER‐007440); Centro 2020 Regional Operational Programme (CENTRO‐01‐0145‐FEDER‐000008: BrainHealth 2020).

Background: The concept 'the retina as a window to the brain' in Alzheimer´s disease (AD) has been explored in recent years since patients sometimes present visual alterations before the first symptoms of dementia. The retina is an extension of the brain and can be assessed by non-invasive methods. However, assessing the retina for AD diagnosis is still a matter of debate. Using the triple transgenic mouse model of AD (3xTg-AD), this study was undertaken to investigate whether the retina and brain undergo similar molecular and cellular changes during the early stages of AD pathology, and if the retina could anticipate the pathological alterations occurring in the brain. Methods: We used the 3xTg-AD and wild-type mice (C57BL6/129S), at 4 and 8 months of age, and assessed several parameters in the retina and brain (hippocampus and cortex): amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau) levels, barrier permeability, cell death, neurotransmitter levels and glial changes. Results: We detected increased Aβ levels in the hippocampus and cortex and increased p-tau in the hippocampus, retina and cortex of 3xTg-AD mice. The brain and retinal barriers were unaffected. At 4 months, the content of some synaptic proteins increased in the brain but not in the retina. No cell death, including retinal ganglion cells loss, was detected in 3xTg-AD mice. Overall, no changes were observed in glutamate and GABA levels in all regions. There was an increase in astrogliosis in the hippocampus at 4 months and a decrease in the retina at 8 months. No changes were detected in Müller cells reactivity. Furthermore, we did not find changes in the number of microglia in 3xTg-AD mice, but we detected a different profile in microglia branching in the hippocampus and retina, at 4 months, where the number and length of the processes increased in the hippocampus and decreased in the retina. Conclusions: At the early stages of pathology, the retina, hippocampus and cortex of 3xTg-AD are not significantly affected, but already present some molecular and cellular alterations. The retina did not mirror the changes detected in the brain in this animal model of familial AD, and these observations should be taking into account when using the retina as a potential diagnostic tool for AD.