1. Dendritic Tau in Alzheimer’s Disease
Arne Ittner, Lars M. Ittner 
Neuron 
Volume 99, Issue 1, Pages (July 2018)
DOI: /j.neuron
Copyright © 2018 Elsevier Inc. Terms and Conditions

2. Figure 1
Tau
(A) The microtubule-associated protein tau is encoded by the MAPT gene and expressed as 6 alternatively spliced isoforms, harboring 0, 1, or 2 amino (N)-terminal inserts (0N, 1N, or 2N) and 3 or 4 repeats (3R or 4R) in the carboxy-terminal part of the protein. The primary sequence of tau comprises an N-terminal half, referred to as “projection domain,” followed by a Proline-rich region. The C-terminal contains the microtubule-binding repeats (MTRs) and is followed by a largely uncharacterized C-terminal tail. Tau is a substrate for a large number of kinases and contains potential 77 Serine/Threonine (positions indicated by blue lines) and 4 Tyrosine phosphorylation sites (dark red lines). Other secondary modifications (e.g., acetylation, ubiquitination) and protease-mediated truncation have been reported and may contribute differentially to disease and to physiological functions of tau.
(B) Kinase/phosphatase activities modulate tau phosphorylation, thereby altering tau’s binding to microtubules (MT). In AD and FTDs, tau becomes progressively phosphorylated at multiple sites. This “hyperphosphorylated” state of tau together with alterations in local environment, chaperone function, cell stress, and other factors make it prone to oligomerization and paired helical filament (PHF) formation, eventually leading to neurofibrillary tangles (NFT).
Neuron  , 13-27DOI: ( /j.neuron )
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3. Figure 2
Key Regulatory Pathways of Dendritic/Post-synaptic Tau Localization
(A) Tau is found predominantly in the axon of neurons, with dendritic spines (post-synapse) being additional sites of tau accumulation. Low levels of tau are found in the soma and the axonal presynaptic terminal. The axon initial segment (AIS) provides a barrier for retrograde diffusion of tau, increasing axonal levels.
(B) Several mechanisms contribute to post-synaptic tau localization: (a) tau binds to components of the post-synaptic density (PSD); (b) microtubule (MT)-dependent tau recruitment to dendrites, mislocalization of axonal/somatic tau, or (c) local translation of tau mRNA in the dendrite contributes to tau protein levels available to post-synapses; (d) tau localization to post-synapses is MT dependent; some tau interaction partners, such as Fyn kinase, require tau binding to MTs for their post-synaptic recruitment; (e) tau levels in the PSD increase upon engagement of NMDA receptors (NMDAR); (f) post-synaptic tau levels are affected by synaptic plasticity with induction of LTP and enhanced surface AMPA receptor (AMPAR) expression increasing tau levels within the PSD.
Neuron  , 13-27DOI: ( /j.neuron )
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4. Figure 3 Post-synaptic Tau Mediates Excitotoxicity
(A) Tau recruits Fyn to NMDAR/PSD-95 complexes and is required to mediate excitotoxicity induced by Aβ and excess glutamate levels. Fyn-conferred NR2B phosphorylation at Y1472 enhances binding of PSD-95 to NMDAR, thereby increasing levels of tau in NMDAR complexes.
(B) Tau limits the binding of SynGAP1 to PSD-95 at post-synaptic NMDAR complexes. SynGAP1 is a local negative regulator of the excitotoxic Ras-Raf-MEK-ERK1/2 pathway at the PSD.
(C) Reducing post-synaptic tau levels by antisense oligonucleotides (ASOs) or gene targeting mitigates excitotoxicity.
Neuron  , 13-27DOI: ( /j.neuron )
Copyright © 2018 Elsevier Inc. Terms and Conditions

5. Figure 4
Post-translational Modifications of Tau in Post-synaptic Signaling
Key sites for phosphorylation in tau that affect post-synaptic mechanisms include S199, S202, T205, and S396.
(A) Phosphorylation of tau at epitopes S199 and S202 compromises its association with the PSD.
(B) Post-synaptic kinase p38γ phosphorylates tau at T205, thereby removing tau from PSD-95/NMDAR complexes. Dissociation of the PSD-95/tau interaction inhibits toxic signals downstream of the NMDAR, including Aβ-type excitotoxicity, by uncoupling tau from downstream factors such as Fyn and ERK.
(C) Engagement of synaptic NMDARs increases activity of GSK3β, which phosphorylates tau at S396. Tau phosphorylated at S396 binds to PICK1, a regulator of AMPA receptors (AMPARs) in synaptic plasticity, resulting in increased internalization of surface AMPAR expressed at the PSD, and thus enhances long-term depression (LTD). Tau acetylation at K274 and K281 regulates long-term potentiation (LTP). Tau acetylation, which is reduced by HDAC6, inhibits the post-synaptic protein KIBRA that facilitates AMPA receptor integration into the PSD during LTP. Thus, tau regulates processes during LTP and AMPAR surface expression in an acetylation-dependent manner.
Neuron  , 13-27DOI: ( /j.neuron )
Copyright © 2018 Elsevier Inc. Terms and Conditions