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In this Research Topic, we wish to summarize and review the etiology of AD and the related therapeutic opportunities for the next decades. To fully understand the precise mechanisms underlying AD, research findings, reviews, new insights and new approaches include AD and related tauopathies, tau phosphorylation balance, pharmacological compounds against AD, neuroprotection strategies and new therapeutic ways but also risk factors for AD and AD genetic information are included in this issue.

Alzheimer's disease --- Research. --- Alzheimer disease --- Alzheimer's dementia --- Basal ganglia --- Presenile dementia --- Senile dementia --- Diseases --- kinase inhibitors --- Therapeutics --- tau --- TREM2 --- Alzheimers disease --- microbiome --- Aβ peptides

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The amyloid precursor protein APP plays a key role in the pathogenesis of Alzheimer’s disease (AD), as proteolytical cleavage of APP gives rise to the Aß peptide which is deposited in the brains of Alzheimer patients. Despite this, our knowledge of the normal cell biological and physiological functions of APP and the closely related APLPs is limited. This may have hampered our understanding of AD, since evidence has accumulated that not only the production of the Aß peptide but also the loss of APP-mediated functions may contribute to AD pathogenesis. Thus, it appears timely and highly relevant to elucidate the functions of the APP gene family from the molecular level to their role in the intact organism, i.e. in the context of nervous system development, synapse formation and adult synapse function, as well as neural homeostasis and aging. Why is our understanding of the APP functions so limited? APP and the APLPs are multifunctional proteins that undergo complex proteolytical processing. They give rise to an almost bewildering array of different fragments that may each subserve specific functions. While Aß is aggregation prone and neurotoxic, the large secreted ectodomain APPsa - produced in the non-amyloidogenic a-secretase pathway - has been shown to be neurotrophic, neuroprotective and relevant for synaptic plasticity, learning and memory. Recently, novel APP cleavage pathways and enzymes have been discovered that have gained much attention not only with respect to AD but also regarding their role in normal brain physiology. In addition to the various cleavage products, there is also solid evidence that APP family proteins mediate important functions as transmembrane cell surface molecules, most notably in synaptic adhesion and cell surface signaling. Elucidating in more detail the molecular mechanisms underlying these divers functions thus calls for an interdisciplinary approach ranging from the structural level to the analysis in model organisms. Thus, in this research topic of Frontiers we compile reviews and original studies, covering our current knowledge of the physiological functions of this intriguing and medically important protein family.

Amyloid precursor-like protein --- learning and memory --- neuroprotection --- spines --- synaptic plasticity --- Alzheimers disease --- animal model --- synaptogenesis --- synaptic adhesion --- Amyloid precursor protein

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During aging, reductions in hippocampal neurogenesis are associated with memory decline indicating a causal relationship. Indeed, insulin-like growth factor-1 (IGF-1), a major activator of the extracellular receptor kinase pathway that is central in learning and memory processes, is also a key modulator of hippocampal neurogenesis. Previously, we showed that age-related declines in spatial memory tasks can be improved by antioxidant-rich diets containing blueberries. In this study, to begin to understand the mechanisms responsible for the beneficial effects of blueberries, we assessed changes in hippocampal plasticity parameters such as hippocampal neurogenesis, extracellular receptor kinase activation, and IGF-1 and IGF-1R levels in blueberry-supplemented aged animals. Our results show that all these parameters of hippocampal neuronal plasticity are increased in supplemented animals and aspects such as proliferation, extracellular receptor kinase activation and IGF-1 and IGF-1R levels correlate with improvements in spatial memory. Therefore, cognitive improvements afforded by polyphenolic-rich fruits such as blueberries appear, in part, to be mediated by their effects on hippocampal plasticity

Activation. --- Adult dentate gyrus. --- Aged rats. --- Aging. --- Alzheimers-disease. --- Animal. --- Animals. --- Antioxidants. --- Behavior. --- Cognition. --- Diet. --- Dietary supplementation. --- Environmental enrichment. --- Erk. --- Growth-factor-i. --- Growth. --- Hippocampal neurogenesis. --- Hippocampal. --- Human. --- Igf-1. --- Learning and memory. --- Learning. --- Level. --- Mechanisms. --- Medial prefrontal cortex. --- Memory. --- Modulation. --- Neurogenesis. --- Neuronal signal-transduction. --- Neuronal. --- Parameters. --- Plasticity. --- Rat. --- Rats. --- Receptor. --- Reduction. --- Spatial memory. --- Spatial. --- Task. --- Tasks. --- Time. --- Vitamin-e. --- Water maze.

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A number of studies have demonstrated that both morphological and biochemical indices in the brain undergo alterations in response to environmental influences. In previous work we have shown that rats raised in an enriched environmental condition (EC) perform better on a spatial memory task than rats raised in isolated conditions (IC), We have also found that EC rats have a higher density of immunoreactivity than IC rats for both low and high affinity nerve growth factor (NGF) receptors in the basal forebrain. In order to determine if these alterations were coupled with altered levels of neurotrophins in other brain regions as well, we measured neurotrophin levels in rats that were raised in EC or IC conditions. Rats were placed in the different environments at 2 months of age and 12 months later brain regions were dissected and analyzed for NGF, brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) levels using Promega ELISA kits. We found that NGF and BDNF levels were increased in the cerebral cortex, hippocampal formation, basal forebrain, and hindbrain in EC animals compared to age-matched IC animals. NT-3 was found to be increased in the basal forebrain and cerebral cortex of EC animals as well. These findings demonstrate significant alterations in NGF, BDNF, and NT-3 protein levels in several brain regions as a result of an enriched versus an isolated environment and thus provide a possible biochemical basis for behavioral and morphological alterations that have been found to occur with a shifting environmental stimulus. (C) 2000 Academic Press

Affinity ngf receptors. --- Age. --- Aged rats. --- Alzheimers-disease. --- Animal. --- Animals. --- Biochemical. --- Brain. --- Cerebral-cortex. --- Cholinergic neuron atrophy. --- Cognitive dysfunction. --- Cortex. --- Density. --- Elisa. --- Enriched. --- Enrichment. --- Environment. --- Environmental enrichment. --- Environments. --- Factor messenger-rna. --- Growth. --- Hippocampal slices. --- Hippocampal-formation. --- Hippocampal. --- Immunoreactivity. --- Increase. --- Increases. --- Learning deficits. --- Level. --- Long-term. --- Memory. --- Nerve growth-factor. --- Neurotrophic factor. --- Neurotrophin,ngf,bdnf,nt-3,elisa,enriched environment. --- Ngf. --- Protein. --- Rat-brain. --- Rat. --- Rats. --- Receptor. --- Receptors. --- Response. --- Spatial memory. --- Spatial. --- Stimulus. --- Task. --- Visual-cortex. --- Work.