Circuitry and Synaptic Dysfunction in Alzheimer’s Disease: A New Tau Hypothesis

<div>Tau phosphorylation and its involvement in long-term depression (LTD). (1) Calmodulin (CaM) detects a Ca<sup>2+</sup> increment due to NMDAr activation, leading to protein phosphatase-2B (PP2B) activation and the subsequent activation of the PP1. (2) PP1 dephosphorylates Ser845 at the AMPAr subunit GluA1, Ser295 at PSD95, and GSK3<i>β</i>. (3) Active GSK3<i>β</i> leads to pTau near MD (microtubule domain). (4) pTau induced LTD by the dissociation of Tau/Fyn/PSD95 complex. (5) Dissociation of Tau/Fyn/PSD95 leads to disruption of interaction between GluA2 and with N-ethylmaleimide-sensitive factor (NSF) that cause clathrin-mediated endocytosis of receptors during NMDAr-LTD. (6) Inactive GSK3<i>β</i> (through the PI3K/AKT pathway) and dephosphorylated Tau (that recruits Fyn kinase to target the PSD95/NMDAr complex) promote long-term potentiation (LTP) (<span class="nowrap"><svg height="8.46387pt" id="M1" style="vertical-align:-0.1802998pt" version="1.1" viewbox="-0.0498162 -8.28357 97.0995 8.46387" width="97.0995pt" xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink"><g transform="matrix(.013,0,0,-0.013,0,0)"><path d="M433 39L423 65C413 59 399 54 387 54C370 54 352 69 352 114V299C352 352 342 392 307 422C285 440 255 449 225 449C168 437 102 399 75 379C56 365 44 353 44 339C44 315 69 296 87 296C101 296 111 303 116 319C124 349 133 371 145 385C156 397 171 404 190 404C241 404 275 364 275 291V274C253 256 180 229 120 209C65 190 39 159 39 110C39 47 88 -12 159 -12C189 -12 237 25 277 52C282 35 288 21 301 8C312 -3 333 -12 348 -12L433 39ZM275 84C256 65 221 48 195 48C164 48 124 73 124 124C124 161 146 180 185 198C206 208 254 229 275 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Neural Plasticity

fig2

Figure 2

Figure 2: Circuitry and Synaptic Dysfunction in Alzheimer’s Disease: A New Tau Hypothesis 