Fig. 5

The mechanotransduction pathway from ECM to synapses failure in Alzheimer’s disease. Grey arrows “↑” and “↓” indicate increase and decrement of quantities; the continuous arrows refer to data from literature; dashed arrows stand for hypothesis; blue arrows represent the connections from literature; the green arrows are the retroaction effects. A ECM stiffness decreases in Alzheimer’s disease. Stimuli from ECM reach the nuclear lamina by integrins, F-actin, nesprins and SUN proteins. B Under mechanical stimuli, the nucleus requires an increase in lamin A quantity to protect the genome (hypothesis not yet verified). C The increase of lamin A exacerbates in blebs and invaginations formation, leading to the nuclear scaffold deformation and bringing to the nuclear pore complexes closure (D). E It causes the impairment of nucleo-cytoplasmic transport of proteins, resulting in proteostasis interruption. F Tau nuclear-cytoplasmic transport is impaired and remains entrapped in the cytoplasmic compartment, causing a pathological accumulation (hypothesis not yet verified). G Hyp-tau localizes also near NPCs, releasing NUP98 in the cytoplasm and further compromising NPCs function. The release of NUP98, accelerates hyp-tau aggregation. H NPCs closure also causes the damage of mRNA transport, which induces PP2A gene translation impairment, a decrement of phosphatase concentration (I) and an increase in tau hyperphosphorylation (J). K The high quantity of tau protein in the cytoplasm combined with tau hyperphosphorylation leads to tau self-aggregation in tangles. Tau tangles interacts stably with pre-synaptic vesicles, impeding the neurotransmitter release into the synaptic space (L). M When tangles affect the motor protein kinesin-mediated transport, kinesin detaches from microtubules and releases the vesicles containing Aβ precursor, resulting in Aβ precursor accumulation. Aβ accumulation compromises oligodendrocytes viability, hindering their production of myelin and contributing to further ECM softening (N). Furthermore, Aβ accumulation reduces tubulin polymerization, leading to dendritic spines signalling loss (O) and alters the physiological long-term potentiation contributing to the synapses loss and progressive memory impairment (P)