Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer's disease (AD) after APOE. We report that BIN1 transcript levels were increased in AD brains and identified a novel 3 bp insertion allele ∼28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14–1.26) (P=3.8 × 10−11)). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology.

Tau transgenic mice are valuable models to investigate the role of tau protein in Alzheimer's disease and other tauopathies. However, motor dysfunction and dystonic posture interfering with behavioral testing are the most common undesirable effects of tau transgenic mice. Therefore, we have generated a novel mouse model (THY-Tau22) that expresses human 4-repeat tau mutated at sites G272V and P301S under a Thy1.2-promotor, displaying tau pathology in the absence of any motor dysfunction. THY-Tau22 shows hyperphosphorylation of tau on several Alzheimer's disease-relevant tau epitopes (AT8, AT100, AT180, AT270, 12E8, taupSer396, and AP422), neurofibrillary tangle-like inclusions (Gallyas and MC1-positive) with rare ghost tangles and PHF-like filaments, as well as mild astrogliosis. These mice also display deficits in hippocampal synaptic transmission and impaired behavior characterized by increased anxiety, delayed learning from 3 months, and reduced spatial memory at 10 months. There are no signs of motor deficits or changes in motor activity at any age investigated. This mouse model therefore displays the main features of tau pathology and several of the pathophysiological disturbances observed during neurofibrillary degeneration. This model will serve as an experimental tool in future studies to investigate mechanisms underlying cognitive deficits during pathogenic tau aggregation. Alzheimer's disease (AD) is the most common form of dementia in the elderly and is characterized neuropathologically by the presence of intracellular neurofibrillary tangles (NFTs) and senile plaques in the brain and by a major loss of synaptic connections. NFTs are neuronal inclusions of the microtubule-associated tau protein and are composed of aggregated phosphorylated tau. In AD, NFTs occur in the hippocampus, the entorhinal and polymodal association cortices, and in the basal forebrain. These brain areas are also severely affected by neuronal and synaptic loss. The loss of neurites, synapses, and neurons represent one of the reasons for the cognitive deficits and dementia of AD.

Microtubule-associated Tau proteins belong to a family of factors that polymerize tubulin dimers and stabilize microtubules. Tau is strongly expressed in neurons, localized in the axon and is essential for neuronal plasticity and network. From the very beginning of Tau discovery, proteomics methods have been essential to the knowledge of Tau biochemistry and biology. In this review, we have summarized the main contributions of several proteomic methods in the understanding of Tau, including expression, post-translational modifications and structure, in both physiological and pathophysiological aspects. Finally, recent advances in proteomics technology are essential to develop further therapeutic targets and early predictive and discriminative diagnostic assays for Alzheimer's disease and related disorders.

Amyloid precursor protein (APP) metabolism is central to the pathogenesis of Alzheimer disease. We showed recently that the amyloid intracellular domain (AICD), which is released by ␥-secretase cleavage of APP C-terminal fragments (CTFs), is strongly increased in cells treated with alkalizing drugs (Vingtdeux, V., Hamdane, M., Bégard, S., Loyens, A., Delacourte, A., Beauvillain, J.-C., Buée, L., Marambaud, P., and Sergeant, N. Amyloid precursor protein (APP)3 metabolism is central to Alzheimer disease etiopathogenesis. Extracellular amyloid deposits, a neuropathological hallmark of Alzheimer disease, are composed of amyloid-␤ (A␤) peptides that derive from APP catabolism. APP is a type I transmembrane glycoprotein processed by an ␣-or a ␤-secretase to produce C-terminal fragments (CTFs) (for review, see Ref. 1). ␥-Secretase further processes APP-CTFs (2, 3), releasing A␤ from ␤-CTF and the amyloid intracellular domain (AICD or ⑀-CTF) from all APP-CTFs (2, 4 -8). Several lines of evidence suggest that AICD is a trans-regulating factor of gene expression (neprilysin, KAI1, APP, and glycogen synthase kinase-3␤) (9 -12). However, AICD is rapidly degraded and thus seldom detected (13). We showed recently that AICD is strongly increased upon treatment with alkalizing drugs, suggesting that the endosomal/lysosomal pathway regulates AICD degradation (14).The endosomal/lysosomal pathway is essential for A␤ production and APP catabolism. For instance, BACE-1 (beta-site APP-cleaving enzyme 1) resides within endosomes, and endocytosis of BACE-1 and APP is a prerequisite for generating A␤ (15-17). An acidic pH is necessary for optimal BACE-1 protease activity (18), and BACE-1 is degraded in lysosomes (19). The ␥-secretase activity has been localized at the endosomal/ lysosomal membrane (20 -23). Treatment with drugs that prevent endosomal/lysosomal acidification (24 -26) or deletion of the APP internalization motif (27, 28) dramatically reduces A␤ secretion.The endosomal/lysosomal system is likely to be altered in Alzheimer disease (for review, see Ref. 29). Several APP derivatives accumulate in multivesicular bodies (MVBs), in transgenic animal models of amyloidosis (30, 31), in Alzheimer disease (30), and in cell models (32). MVBs belong to the endocytic pathway (33); are at the crossroad of several cellular mechanisms such as membrane receptor recycling and protein degradation; and can release their intraluminal vesicles, known as exosomes (for review, see Refs. 34 -36). More recently, exosomes were demonstrated to contain A␤ peptides (37). Taken together, a growing body of evidence suggests that APP processing takes place mainly between the plasma membrane and late endosomal compartments such as multivesicular endosomes. Herein, we studied the localization of APP and its derivatives in SY5Y neuroblastoma cells stably overexpressing human APP and demonstrate that APP, APP-CTFs, and AICD accumulate in the luminal vesicles of multivesicular endosomes and are also found in exosomes.

Physiological functions of tau remain ill defined. In the present study, Marciniak et al. uncover a novel function of tau in its ability to regulate brain insulin signaling and discuss the pathophysiological implications of these findings for Alzheimer’s disease and tauopathies.

Consumption of caffeine, a non-selective adenosine A2A receptor (A2AR) antagonist, reduces the risk of developing Alzheimer's disease (AD) in humans and mitigates both amyloid and Tau burden in transgenic mouse models. However, the impact of selective A2AR blockade on the progressive development of AD-related lesions and associated memory impairments has not been investigated. In the present study, we removed the gene encoding A2AR from THY-Tau22 mice and analysed the subsequent effects on both pathological (Tau phosphorylation and aggregation, neuro-inflammation) and functional impairments (spatial learning and memory, hippocampal plasticity, neurotransmitter profile). We found that deleting A2ARs protect from Tau pathology-induced deficits in terms of spatial memory and hippocampal long-term depression. These effects were concomitant with a normalization of the hippocampal glutamate/gamma-amino butyric acid ratio, together with a global reduction in neuro-inflammatory markers and a decrease in Tau hyperphosphorylation. Additionally, oral therapy using a specific A2AR antagonist (MSX-3) significantly improved memory and reduced Tau hyperphosphorylation in THY-Tau22 mice. By showing that A2AR genetic or pharmacological blockade improves the pathological phenotype in a Tau transgenic mouse model, the present data highlight A2A receptors as important molecular targets to consider against AD and Tauopathies.

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