A similar finding of

altered APP localization to endosomes was also described in the context of iPSC-derived neurons from familial AD associated with a duplication of the APP locus (Israel et al., 2012). Of note, the APP cellular relocalization phenotype is not simply a secondary effect of increased Aβ production, as pharmacological blockade of APP processing failed to suppress the modified APP localization. Genetic “rescue” studies, in which wild-type PSEN1 overexpressed in the PSEN1 mutant hiN cultures suppressed the disease-associated Selleckchem Regorafenib phenotypes, support a direct role for PSEN1 mutation in the phenotype of PSEN1 mutant cells, rather than a spurious effect due to unrelated common variants that may be present in these cultures ( Qiang

et al., 2011). These initial studies with human neuron models of familial AD supported the notion that processes other than extracellular Aβ fragment accumulation may play a role in AD pathology. To further address this, Kondo et al. (2013) used human iPSC-derived forebrain cortical neurons that harbor an APP mutation, V717L, also associated with a familial clinical dementia syndrome of the Alzheimer’s type, Fulvestrant price but one that appears to lack the typical amyloid plaques, composed largely of extracellular Aβ42. iPSC-derived neurons from patients with the V717L APP mutation showed reduced extracellular Aβ42 and Aβ40, consistent with the CNS pathology in human patients with this mutation. Interestingly, intracellular accumulation of Aβ forms was increased (Kondo et al., 2013), suggesting an alternative mechanism of pathology. The increase intracellular Aβ was correlated with markers of endoplasmic reticulum (ER)

and oxidative stress, as well as apoptosis, in the iPSC-derived neuron cultures carrying the V717L mutation. Docosahexaenoic acid (DHA), a therapeutic candidate for AD, relieved the ER stress responses and suppressed apoptosis in the mutant cells. An additional pathological finding that typifies AD patient brain is the accumulation of modified, hyperphosphorylated, and aggregated TAU protein, leading to the L-NAME HCl accumulation of neurofibrillary tangles. APP mutant human iPSC-derived neuron cultures have been reported to harbor increased TAU phosphorylation (Israel et al., 2012), whereas the majority of transgenic rodent models fail to do so, likely reflecting species differences in the TAU gene. Interestingly, inhibition of γ-secretase—which is required for Aβ fragment generation—failed to suppress such phospho-TAU pathology in iPSC-derived APP mutant neurons, whereas inhibition of β-secretase function appeared effective ( Israel et al., 2012). As inhibition of either secretase complex suppresses Aβ production, this finding further supported the notion that aspects of APP biology other than extracellular Aβ accumulation may play an important role in AD pathology.