Organ-Derived Extracellular Matrix (ECM) Hydrogels: Versatile Systems to Investigate the Impact of Biomechanics and Biochemistry on Cells in Disease Pathology:Handbook of the Extracellular Matrix

The extracellular matrix (ECM) provides instructive and constructive support to cells in all organs. The ECM’s composition and structure are organ-dependent. The adhesion of cells to ECM with, e.g., integrins triggers cellular mechanosignalling. The role of mechanical properties of ECM hydrogels in vivo remains scarce. To replicate the ECM-cell interactions requires organ and tissue-specific ECM hydrogels. Such 3D culture systems allow the monitoring of ECM dynamics, i.e., turnover and mechanical changes (stiffness and stress relaxation). Compression testing allows to determine stiffness and stress relaxation. Hydrogels’ stress relaxation is governed by displacement of water, large macromolecules, and cells in a time- and organ origin-dependent fashion. The ECM biochemistry also regulates cell fate and function, e.g., through integrin signalling and via small molecules like growth factors that bind to specific ECM components. Organ-derived ECM hydrogels gain increasing interest due to their promising prospects for clinical use to augment tissue regeneration

Rac1b increases with progressive tau pathology within cholinergic nucleus basalis neurons in alzheimer\u27s disease

Cholinergic basal forebrain (CBF) nucleus basalis (NB) neurons display neurofibrillary tangles (NFTs) during Alzheimer\u27s disease (AD) progression, yet the mechanisms underlying this selective vulnerability are currently unclear. Rac1, a member of the Rho family of GTPases, may interact with the proapoptotic pan-neurotrophin receptor p75 NTR to induce neuronal cytoskeletal abnormalities in AD NB neurons. Herein, we examined the expression of Rac1b, a constitutively active splice variant of Rac1, in NB cholinergic neurons during AD progression. CBF tissues harvested from people who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment, or AD were immunolabeled for both p75 NTR and Rac1b. Rac1b appeared as cytoplasmic diffuse granules, loosely aggregated filaments, or compact spheres in p75 NTR-positive NB neurons. Although Rac1b colocalized with tau cytoskeletal markers, the percentage of p75 NTR-immunoreactive neurons expressing Rac1b was significantly increased only in AD compared with both mild cognitive impairment and NCI. Furthermore, single-cell gene expression profiling with custom-designed microarrays showed down-regulation of caveolin 2, GNB4, and lipase A in AD Rac1b-positive/p75 NTR-labeled NB neurons compared with Rac1b-negative/p75 NTR-positive perikarya in NCI. These proteins are involved in Rac1 pathway/cell cycle progression and lipid metabolism. These data suggest that Rac1b expression acts as a modulator or transducer of various signaling pathways that lead to NFT formation and membrane dysfunction in a subgroup of CBF NB neurons in AD. © 2012 American Society for Investigative Pathology