Candidate-based screening via gene modulation in human neurons and astrocytes implicates FERMT2 in Aß and TAU proteostasis.

Large-scale 'omic' studies investigating the pathophysiological processes that lead to Alzheimer's disease (AD) dementia have identified an increasing number of susceptibility genes, many of which are poorly characterized and have not previously been implicated in AD. Here, we evaluated the utility of human induced pluripotent stem cell-derived neurons and astrocytes as tools to systematically test AD-relevant cellular phenotypes following perturbation of candidate genes identified by genome-wide studies. Lentiviral-mediated delivery of shRNAs was used to modulate expression of 66 genes in astrocytes and 52 genes in induced neurons. Five genes (CNN2, GBA, GSTP1, MINT2 and FERMT2) in neurons and nine genes (CNN2, ITGB1, MINT2, SORL1, VLDLR, NPC1, NPC2, PSAP and SCARB2) in astrocytes significantly altered extracellular amyloid-ß (Aß) levels. Knockdown of AP3M2, CNN2, GSTP1, NPC1, NPC2, PSAP and SORL1 reduced interleukin-6 levels in astrocytes. Only knockdown of FERMT2 led to a reduction in the proportion of TAU that is phosphorylated. Further, CRISPR-Cas9 targeting of FERMT2 in both familial AD (fAD) and fAD-corrected human neurons validated the findings of reduced extracellular Aß. Interestingly, FERMT2 reduction had no effect on the Aß42:40 ratio in corrected neurons and a reduction of phospho-tau, but resulted in an elevation in Aß42:40 ratio and no reduction in phospho-tau in fAD neurons. Taken together, this study has prioritized 15 genes as being involved in contributing to Aß accumulation, phosphorylation of tau and/or cytokine secretion, and, as illustrated with FERMT2, it sets the stage for further cell-type-specific dissection of the role of these genes in AD.

Epigenome-wide study uncovers large-scale changes in histone acetylation driven by tau pathology in aging and Alzheimer's human brains.

Accumulation of tau and amyloid-ß are two pathologic hallmarks of Alzheimer's disease. We conducted an epigenome-wide association study using the histone 3 lysine 9 acetylation (H3K9ac) mark in 669 aged human prefrontal cortices; in contrast with amyloid-ß, tau protein burden had a broad effect on the epigenome, affecting 5,990 of 26,384 H3K9ac domains. Tau-related alterations aggregated in large genomic segments reflecting spatial chromatin organization, and the magnitude of these effects correlated with the segment's nuclear lamina association. Functional relevance of these chromatin changes was demonstrated by (1) consistent transcriptional changes in three independent datasets and (2) similar findings in two mouse models of Alzheimer's disease. Finally, we found that tau overexpression in induced pluripotent stem cell-derived neurons altered chromatin structure and that these effects could be blocked by a small molecule predicted to reverse the tau effect. Thus, we report broad tau-driven chromatin rearrangements in the aging human brain that may be reversible with heat-shock protein 90 (Hsp90) inhibitors.

Racial and socioeconomic differences in psychiatric symptoms in nursing home residents: a minimum data set-based pilot study.

BACKGROUND: Little research has explored racial and socioeconomic differences in the presence, detection, and treatment of neuropsychiatric symptoms in nursing home residents. OBJECTIVE: To evaluate racial and socioeconomic differences on mood and behavior Minimum Data Set (MDS) recorded symptoms, MDS recorded psychiatric diagnoses, and MDS identified psychotropic medication use. METHODS: Data were obtained through a cross-sectional review of MDS data of 290 African-American and white residents of 2 nursing homes. The association between age, gender, race, and pay status with mood and behavior patterns, psychiatric diagnoses, and use of psychotropic medication was evaluated. RESULTS: White residents were more likely than African American residents to have MDS recorded psychiatric diagnoses (odds ratio, OR = 3.24), but there were no significant racial differences in recorded mood or behavior symptomatology or in the pharmacologic treatment of mental illness. Medicaid recipients were more likely than nonrecipients to have behavior symptoms (OR = 2.09), have a psychiatric diagnosis (OR = 2.91), and receive psychotropic medications in the absence of a psychiatric diagnosis (OR = 3.62). CONCLUSION: Pay status was associated with recorded symptoms, diagnoses, and medications, but racial differences were found only for recorded diagnoses.