Activated microglia cause metabolic disruptions in developmental cortical interneurons that persist in interneurons from individuals with schizophrenia.

The mechanisms by which prenatal immune activation increase the risk for neuropsychiatric disorders are unclear. Here, we generated developmental cortical interneurons (cINs)-which are known to be affected in schizophrenia (SCZ) when matured-from induced pluripotent stem cells (iPSCs) derived from healthy controls (HCs) and individuals with SCZ and co-cultured them with or without activated microglia. Co-culture with activated microglia disturbed metabolic pathways, as indicated by unbiased transcriptome analyses, and impaired mitochondrial function, arborization, synapse formation and synaptic GABA release.

Correction: iPSC-derived homogeneous populations of developing schizophrenia cortical interneurons have compromised mitochondrial function.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

iPSC-derived homogeneous populations of developing schizophrenia cortical interneurons have compromised mitochondrial function.

Schizophrenia (SCZ) is a neurodevelopmental disorder. Thus, studying pathogenetic mechanisms underlying SCZ requires studying the development of brain cells. Cortical interneurons (cINs) are consistently observed to be abnormal in SCZ postmortem brains.

Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell-derived cortical interneurons from subjects with schizophrenia.

We generated cortical interneurons (cINs) from induced pluripotent stem cells derived from 14 healthy controls and 14 subjects with schizophrenia. Both healthy control cINs and schizophrenia cINs were authentic, fired spontaneously, received functional excitatory inputs from host neurons, and induced GABA-mediated inhibition in host neurons in vivo. However, schizophrenia cINs had dysregulated expression of protocadherin genes, which lie within documented schizophrenia loci.

Oligodendrocyte differentiation of induced pluripotent stem cells derived from subjects with schizophrenias implicate abnormalities in development.

Abnormalities of brain connectivity and signal transduction are consistently observed in individuals with schizophrenias (SZ). Underlying these anomalies, convergent in vivo, post mortem, and genomic evidence suggest abnormal oligodendrocyte (OL) development and function and lower myelination in SZ. Our primary hypothesis was that there would be abnormalities in the number of induced pluripotent stem (iPS) cell-derived OLs from subjects with SZ.

Late-onset Alzheimer's disease is associated with inherent changes in bioenergetics profiles.

Body-wide changes in bioenergetics, i.e., energy metabolism, occur in normal aging and disturbed bioenergetics may be an important contributing mechanism underlying late-onset Alzheimer's disease (LOAD).

Sprouty2 in the dorsal hippocampus regulates neurogenesis and stress responsiveness in rats.

Both the development and relief of stress-related psychiatric conditions such as major depression (MD) and post-traumatic stress disorder (PTSD) have been linked to neuroplastic changes in the brain. One such change involves the birth of new neurons (neurogenesis), which occurs throughout adulthood within discrete areas of the mammalian brain, including the dorsal hippocampus (HIP). Stress can trigger MD and PTSD in humans, and there is considerable evidence that it can decrease HIP neurogenesis in laboratory animals.

MiR-126 Regulates Growth Factor Activities and Vulnerability to Toxic Insult in Neurons.

Dysfunction of growth factor (GF) activities contributes to the decline and death of neurons during aging and in neurodegenerative diseases. In addition, neurons become more resistant to GF signaling with age. Micro (mi)RNAs are posttranscriptional regulators of gene expression that may be crucial to age- and disease-related changes in GF functions.

Abnormalities in mitochondrial structure in cells from patients with bipolar disorder.

Postmortem, genetic, brain imaging, and peripheral cell studies all support decreased mitochondrial activity as a factor in the manifestation of Bipolar Disorder (BD). Because abnormal mitochondrial morphology is often linked to altered energy metabolism, we investigated whether changes in mitochondrial structure were present in brain and peripheral cells of patients with BD. Mitochondria from patients with BD exhibited size and distributional abnormalities compared with psychiatrically-healthy age-matched controls.

Rab5 mediates an amyloid precursor protein signaling pathway that leads to apoptosis.

Alzheimer's disease (AD) involves activation of apoptotic pathways that may be regulated through signaling cascades initiated by the amyloid precursor protein (APP). Enlarged endosomes have been observed in postmortem AD brains at very early stages of the disease. We show here that exogenous expression of a familial AD (FAD) mutant of APP or of the APP binding protein APP-BP1 in neurons causes enlargement of early endosomes, increased receptor-mediated endocytosis via a pathway dependent on APP-BP1 binding to APP, and apoptosis.

APP-BP1 inhibits Abeta42 levels by interacting with Presenilin-1.

Background: The beta-amyloid precursor protein (APP) is sequentially cleaved by the beta- and then gamma-secretase to generate the amyloid beta-peptides Abeta40 and Abeta42. Increased Abeta42/Abeta40 ratios trigger amyloid plaque formations in Alzheimer's disease (AD). APP binds to APP-BP1, but the biological consequence is not well understood.

Dysfunction of amyloid precursor protein signaling in neurons leads to DNA synthesis and apoptosis.

The classic neuropathological diagnostic markers for AD are amyloid plaques and neurofibrillary tangles, but their role in the etiology and progression of the disease remains incompletely defined. Research over the last decade has revealed that cell cycle abnormalities also represent a major neuropathological feature of AD. These abnormalities appear very early in the disease process, prior to the appearance of plaques and tangles; and it has been suggested that neuronal cell cycle regulatory failure may be a significant component of the pathogenesis of AD.

The cell cycle as a therapeutic target for Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease worldwide. It is a progressive, incurable disease whose predominant clinical manifestation is memory loss, and which always ends in death. The classic neuropathological diagnostic markers for AD are amyloid plaques and neurofibrillary tangles, but our understanding of the role that these features of AD play in the etiology and progression of the disease remains incomplete.

APP-BP1 mediates APP-induced apoptosis and DNA synthesis and is increased in Alzheimer's disease brain.

APP-BP1, first identified as an amyloid precursor protein (APP) binding protein, is the regulatory subunit of the activating enzyme for the small ubiquitin-like protein NEDD8. We have shown that APP-BP1 drives the S- to M-phase transition in dividing cells, and causes apoptosis in neurons. We now demonstrate that APP-BP1 binds to the COOH-terminal 31 amino acids of APP (C31) and colocalizes with APP in a lipid-enriched fraction called lipid rafts.

DNA synthesis and neuronal apoptosis caused by familial Alzheimer disease mutants of the amyloid precursor protein are mediated by the p21 activated kinase PAK3.

Apoptotic pathways and DNA synthesis are activated in neurons in the brains of individuals with Alzheimer disease (AD). However, the signaling mechanisms that mediate these events have not been defined. We show that expression of familial AD (FAD) mutants of the amyloid precursor protein (APP) in primary neurons in culture causes apoptosis and DNA synthesis.

Abeta42 generation is toxic to endothelial cells and inhibits eNOS function through an Akt/GSK-3beta signaling-dependent mechanism.

The application of beta-amyloid (Abeta) is cytotoxic to endothelial cells, promotes vasoconstriction and impairs nitric oxide (NO) generation or action. However, there is no information on the effect of intracellular Abeta on endothelial cell biology, although recent studies indicate that neuronal Abeta drives Alzheimer's disease pathogenesis. Since the serine-threonine kinase Akt is crucial to both neuronal and endothelial cell survival as well as eNOS activation, we investigated the effects of Abeta expression on Akt-signaling in cultured endothelial cells.