A monoclonal antibody to the microtubuleassociated protein X (tau) labeled some neurofibrillary tangles and plaque neurites, the two major locations of paired-helical

on Defeating Alzheimer's Disease and other dementias: a priority for European science and society Dementia includes a range of neurological disorders characterized by memory loss and cognitive impairment. The most common early symptom is difficulties remembering recent events. With the development of the disease, symptoms occur such as disorientation, mood swings, confusion, more serious memory loss, behavioural changes, difficulties in speaking and swallowing, as well as walking. Alzheimer Disease (AD) is the most common form of dementia (50-70% of dementia cases). Increasing age is the most important risk factor for AD.In 2012 and 2015, the World Health Organization (WHO) presented reports suggesting that Alzheimer Disease and other dementias (ADOD) should be regarded as a global public health priority 1,2 . Similar policy declarations have been presented by the European Union 3 , as well as by some individual countries. These policy declarations acknowledge trends that sometimes are described in terms of an epidemic or a "time-bomb". In 2015, the number of people affected by dementia worldwide is estimated to be almost 47 million and the numbers are expected to reach 75 million by 2030 and 131 million by 2050, with the greatest increase in low and middle income countries. The main reason for the increase is the global aging trend, since dementias are associated with a high age-specific prevalence, i.e., increasing prevalence with higher age. The global economic costs of dementia were estimated to be more than 600 billion USD in 2010 6 and 818 billion USD in 2015 5 . The direct costs in the medical and social care sectors, 487 billion USD, represent 0.65% of the aggregated global gross domestic products (GDP), which is an enormous economic impact of a single group of disorders, especially considering that 87% of the costs occur in high income countries. Care of people with dementia impacts several sectors in the society with the social care (long term care and home services) and informal care sectors constituting the greatest proportions -even greater than direct medical care 6 . In cost of illness studies, European cost estimates in 2010 ranged between 238,6 billion USD 6 and 105,6 billion € 7 .However, the economic and societal burden of ADOD corresponds to the aggregate burden of people with dementia and their next of kin. The progressive nature of dementia can influence the whole life situation for families over many years. So far, no cure or substantial symptom relieving treatment is available for ADOD. Thus, the impact of this terminal disease is already today enormous, and given the predictions for the future, ADOD represents an enormous challenge for any society, and particularly to the ageing European society.Further knowledge is needed regarding the causes of ADOD. A more complete understanding of the disease mechanisms is required for new diagnostic and therapeutic strategies. There is also a need to establish new cell-based and animal models representing, as far as possible, major clinical component...

The microtubule-associated protein is a family of six isoforms that becomes abnormally hyperphosphorylated and accumulates in the form of paired helical filaments (PHF) in the brains of patients with Alzheimer's disease (AD) and patients with several other tauopathies. Here, we show that the abnormally hyperphosphorylated from AD brain cytosol (AD P-) self-aggregates into PHF-like structures on incubation at pH 6.9 under reducing conditions at 35°C during 90 min. In vitro dephosphorylation, but not deglycosylation, of AD P-inhibits its self-association into PHF. Furthermore, hyperphosphorylation induces self-assembly of each of the six isoforms into tangles of PHF and straight filaments, and the microtubule binding domains͞repeats region in the absence of the rest of the molecule can also self-assemble into PHF. Thus, it appears that self-assembles by association of the microtubule binding domains͞repeats and that the abnormal hyperphosphorylation promotes the self-assembly of into tangles of PHF and straight filaments by neutralizing the inhibitory basic charges of the flanking regions.

Just as neuronal activity is essential to normal brain function, microtubule-associated protein tau appears to be critical to normal neuronal activity in the mammalian brain, especially in the evolutionary most advanced species, the homo sapiens. While the loss of functional tau can be compensated by the other two neuronal microtubule-associated proteins, MAP1A/MAP1B and MAP2, it is the dysfunctional, i.e., the toxic tau, which forces an affected neuron in a long and losing battle resulting in a slow but progressive retrograde neurodegeneration. It is this pathology which is characteristic of Alzheimer disease (AD) and other tauopathies. To date, the most established and the most compelling cause of dysfunctional tau in AD and other tauopathies is the abnormal hyperphosphorylation of tau. The abnormal hyperphosphorylation not only results in the loss of tau function of promoting assembly and stabilizing microtubules but also in a gain of a toxic function whereby the pathological tau sequesters normal tau, MAP1A/MAP1B and MAP2, and causes inhibition and disruption of microtubules. This toxic gain of function of the pathological tau appears to be solely due to its abnormal hyperphosphorylation because dephosphorylation converts it functionally into a normal-like state. The affected neurons battle the toxic tau both by continually synthesizing new normal tau and as well as by packaging the abnormally hyperphosphorylated tau into inert polymers, i.e., neurofibrillary tangles of paired helical filaments, twisted ribbons and straight filaments. Slowly but progressively, the affected neurons undergo a retrograde degeneration. The hyperphosphorylation of tau results both from an imbalance between the activities of tau kinases and tau phosphatases and as well as changes in tau's conformation which affect its interaction with these enzymes. A decrease in the activity of protein phosphatase-2A (PP-2A) in AD brain and certain missense mutations seen in frontotemporal dementia promotes the abnormal hyperphosphorylation of tau. Inhibition of this tau abnormality is one of the most promising therapeutic approaches to AD and other tauopathies.

Tau is the major microtubule associated protein (MAP) of a mature neuron. The other two neuronal MAPs are MAP1 and MAP2. An established function of MAPs is their interaction with tubulin and promotion of its assembly into microtubules and stabilization of the microtubule network. The microtubule assembly promoting activity of tau, a phosphoprotein, is regulated by its degree of phosphorylation. Normal adult human brain tau contains 2–3 moles phosphate/mole of tau protein. Hyperphosphorylation of tau depresses this biological activity of tau. In Alzheimer disease (AD) brain tau is ∼three to four-fold more hyperphosphorylated than the normal adult brain tau and in this hyperphosphorylated state it is polymerized into paired helical filaments ([PHF) admixed with straight filaments (SF) forming neurofibrillary tangles. Tau is transiently hyperphosphorylated during development and during anesthesia and hypothermia but not to the same state as in AD brain. The abnormally hyperphosphorylated tau in AD brain is distinguished from transiently hyperphosphorylated tau by its ability (1) to sequester normal tau, MAP1 and MAP2 and disrupt microtubules, and (2) to self-assemble into PHF/SF. The cytosolic abnormally hyperphosphorylated tau, because of oligomerization, unlike normal tau, is sedimentable and on self-assembly into PHF/SF, loses its ability to sequester normal MAPs. Some of the tau in AD brain is truncated which also promotes its self-assembly. Tau mutations found in frontotemporal dementia apparently promote its abnormal hyperphosphorylation. Thus, the AD abnormally hyperphosphorylated tau (1) is distinguishable from both normal and transiently hyperphosphorylated taus, and (2) is inhibitory when in a cytosolic/oligomeric state but not when it is self-assembled into PHF/SF. Inhibition of abnormal hyperphosphorylation of tau offers a promising therapeutic target for AD and related tauopathies.

Microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in brains of individuals with Alzheimer's disease (AD) and other tauopathies. Tau pathology is critical to pathogenesis and correlates to the severity of dementia. However, the mechanisms leading to abnormal hyperphosphorylation are unknown. Here, we demonstrate that human brain tau was modified by O-GlcNAcylation, a type of protein O-glycosylation by which the monosaccharide ␤-N-acetylglucosamine (GlcNAc) attaches to serine͞threonine residues via an O-linked glycosidic bond. O-GlcNAcylation regulated phosphorylation of tau in a site-specific manner both in vitro and in vivo. At most of the phosphorylation sites, O-GlcNAcylation negatively regulated tau phosphorylation. In an animal model of starved mice, low glucose uptake͞metabolism that mimicked those observed in AD brain produced a decrease in O-GlcNAcylation and consequent hyperphosphorylation of tau at the majority of the phosphorylation sites. The O-GlcNAcylation level in AD brain extracts was decreased as compared to that in controls. These results reveal a mechanism of regulation of tau phosphorylation and suggest that abnormal hyperphosphorylation of tau could result from decreased tau O-GlcNAcylation, which probably is induced by deficient brain glucose uptake͞metabolism in AD and other tauopathies.

The aim of this systematic review and meta-analysis was to synthesize the knowledge about the relation between intake of 12 major food groups and risk of type 2 diabetes (T2D). We conducted a systematic search in PubMed, Embase, Medline (Ovid), Cochrane Central, and Google Scholar for prospective studies investigating the association between whole grains, refined grains, vegetables, fruits, nuts, legumes, eggs, dairy, fish, red meat, processed meat, and sugar-sweetened beverages (SSB) on risk of T2D. Summary relative risks were estimated using a random effects model by contrasting categories, and for linear and non-linear dose–response relationships. Six out of the 12 food-groups showed a significant relation with risk of T2D, three of them a decrease of risk with increasing consumption (whole grains, fruits, and dairy), and three an increase of risk with increasing consumption (red meat, processed meat, and SSB) in the linear dose–response meta-analysis. There was evidence of a non-linear relationship between fruits, vegetables, processed meat, whole grains, and SSB and T2D risk. Optimal consumption of risk-decreasing foods resulted in a 42% reduction, and consumption of risk-increasing foods was associated with a threefold T2D risk, compared to non-consumption. The meta-evidence was graded “low” for legumes and nuts; “moderate” for refined grains, vegetables, fruit, eggs, dairy, and fish; and “high” for processed meat, red meat, whole grains, and SSB. Among the investigated food groups, selecting specific optimal intakes can lead to a considerable change in risk of T2D.Electronic supplementary materialThe online version of this article (doi:10.1007/s10654-017-0246-y) contains supplementary material, which is available to authorized users.

Abnormal hyperphosphorylation of tau is believed to lead to neurofibrillary degeneration in Alzheimer's disease (AD) and other tauopathies. Recent studies have shown that protein phosphatases (PPs) PP1, PP2A, PP2B and PP5 dephosphorylate tau in vitro, but the exact role of each of these phosphatases in the regulation of site-specific phosphorylation of tau in the human brain was unknown. Hence, we investigated the contributions of these PPs to the regulation of tau phosphorylation quantitatively. We found that these four phosphatases all dephosphorylated tau at Ser199, Ser202, Thr205, Thr212, Ser214, Ser235, Ser262, Ser396, Ser404 and Ser409, but with different efficiencies toward different sites. The K(m) values of tau dephosphorylation catalysed by PP1, PP2A and PP5 were 8-12 microm, similar to the intraneuronal tau concentration of human brain, whereas the K(m) of PP2B was fivefold higher. PP2A, PP1, PP5 and PP2B accounted for approximately 71%, approximately 11%, approximately 10% and approximately 7%, respectively, of the total tau phosphatase activity of human brain. The total phosphatase activity and the activities of PP2A and PP5 toward tau were significantly decreased, whereas that of PP2B was increased in AD brain. PP2A activity negatively correlated to the level of tau phosphorylation at the most phosphorylation sites in human brains. Our findings indicate that PP2A is the major tau phosphatase that regulates its phosphorylation at multiple sites in human brain. The abnormal hyperphosphorylation of tau is partially due to a downregulation of PP2A activity in AD brain.