Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy.

Alzheimer's disease (AD) is characterized by amyloid plaques and neurofibrillary tangles, in addition to neuroinflammation and changes in brain lipid metabolism. 25-Hydroxycholesterol (25-HC), a known modulator of both inflammation and lipid metabolism, is produced by cholesterol 25-hydroxylase encoded by Ch25h expressed as a "disease-associated microglia" signature gene. However, whether Ch25h influences tau-mediated neuroinflammation and neurodegeneration is unknown.

Regulation of astrocyte lipid metabolism and ApoE secretionby the microglial oxysterol, 25-hydroxycholesterol.

Neuroinflammation, a major hallmark of Alzheimer's disease and several other neurological and psychiatric disorders, is often associated with dysregulated cholesterol metabolism. Relative to homeostatic microglia, activated microglia express higher levels of Ch25h, an enzyme that hydroxylates cholesterol to produce 25-hydroxycholesterol (25HC). 25HC is an oxysterol with interesting immune roles stemming from its ability to regulate cholesterol metabolism.

Preclinical Alzheimer's disease biomarkers accurately predict cognitive and neuropathological outcomes.

Alzheimer's disease biomarkers are widely accepted as surrogate markers of underlying neuropathological changes. However, few studies have evaluated whether preclinical Alzheimer's disease biomarkers predict Alzheimer's neuropathology at autopsy. We sought to determine whether amyloid PET imaging or CSF biomarkers accurately predict cognitive outcomes and Alzheimer's disease neuropathological findings.

Cognitively normal APOE ε4 carriers have specific elevation of CSF SNAP-25.

Cerebrospinal fluid (CSF) synaptosomal-associated protein 25 (SNAP-25) and neurogranin (Ng) are recently described biomarkers for pre- and postsynaptic integrity known to be elevated in symptomatic Alzheimer disease (AD). Their relationship with Apolipoprotein E (APOE) ε4 carrier status, the major genetic risk factor for AD, remains unclear. In this study, CSF SNAP-25 and Ng were compared in cognitively normal APOE ε4 carriers and noncarriers (n = 274, mean age 65 ± 9.

Alzheimer Disease: An Update on Pathobiology and Treatment Strategies.

Alzheimer disease (AD) is a heterogeneous disease with a complex pathobiology. The presence of extracellular β-amyloid deposition as neuritic plaques and intracellular accumulation of hyperphosphorylated tau as neurofibrillary tangles remains the primary neuropathologic criteria for AD diagnosis. However, a number of recent fundamental discoveries highlight important pathological roles for other critical cellular and molecular processes.

Novel upregulation of amyloid-β precursor protein (APP) by microRNA-346 via targeting of APP mRNA 5'-untranslated region: Implications in Alzheimer's disease.

In addition to the devastating symptoms of dementia, Alzheimer's disease (AD) is characterized by accumulation of the processing products of the amyloid-β (Aβ) peptide precursor protein (APP). APP's non-pathogenic functions include regulating intracellular iron (Fe) homeostasis. MicroRNAs are small (~ 20 nucleotides) RNA species that instill specificity to the RNA-induced silencing complex (RISC).

Autoimmune Dementia.

Dementia refers to an acquired syndrome of intraindividual cognitive decline that ultimately interferes with an individual's ability to manage their usual duties at work or home. As experience with the diagnosis and management of patients with autoimmune and paraneoplastic encephalitis (AE) has expanded, it has become increasingly apparent that dementia may arise as a subacute or chronic complication of immune-mediated injury to the central nervous system. Progressive memory and thinking problems may represent the first (or only) sign of an underlying autoimmune or paraneoplastic disease.

Human primary mixed brain cultures: preparation, differentiation, characterization and application to neuroscience research.

Background: Culturing primary cortical neurons is an essential neuroscience technique. However, most cultures are derived from rodent brains and standard protocols for human brain cultures are sparse. Herein, we describe preparation, maintenance and major characteristics of a primary human mixed brain culture, including neurons, obtained from legally aborted fetal brain tissue.

Lessons from a BACE1 inhibitor trial: off-site but not off base.

Alzheimer's disease (AD) is characterized by formation of neuritic plaque primarily composed of a small filamentous protein called amyloid-β peptide (Aβ). The rate-limiting step in the production of Aβ is the processing of Aβ precursor protein (APP) by β-site APP-cleaving enzyme (BACE1). Hence, BACE1 activity plausibly plays a rate-limiting role in the generation of potentially toxic Aβ within brain and the development of AD, thereby making it an interesting drug target.

MicroRNA-339-5p down-regulates protein expression of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) in human primary brain cultures and is reduced in brain tissue specimens of Alzheimer disease subjects.

Alzheimer disease (AD) results, in part, from the excess accumulation of the amyloid-β (Aβ) peptide as neuritic plaques in the brain. The short Aβ peptide is derived from the large transmembrane Aβ precursor protein (APP). The rate-limiting step in the production of Aβ from APP is mediated by the β-site APP-cleaving enzyme 1 (BACE1).

MicroRNA-153 physiologically inhibits expression of amyloid-β precursor protein in cultured human fetal brain cells and is dysregulated in a subset of Alzheimer disease patients.

Regulation of amyloid-β (Aβ) precursor protein (APP) expression is complex. MicroRNAs (miRNAs) are expected to participate in the molecular network that controls this process. The composition of this network is, however, still undefined.

Advances in microRNA experimental approaches to study physiological regulation of gene products implicated in CNS disorders.

The central nervous system (CNS) is a remarkably complex organ system, requiring an equally complex network of molecular pathways controlling the multitude of diverse, cellular activities. Gene expression is a critical node at which regulatory control of molecular networks is implemented. As such, elucidating the various mechanisms employed in the physiological regulation of gene expression in the CNS is important both for establishing a reference for comparison to the diseased state and for expanding the set of validated drug targets available for disease intervention.

Increased secreted amyloid precursor protein-α (sAPPα) in severe autism: proposal of a specific, anabolic pathway and putative biomarker.

Autism is a neurodevelopmental disorder characterized by deficits in verbal communication, social interactions, and the presence of repetitive, stereotyped and compulsive behaviors. Excessive early brain growth is found commonly in some patients and may contribute to disease phenotype. Reports of increased levels of brain-derived neurotrophic factor (BDNF) and other neurotrophic-like factors in autistic neonates suggest that enhanced anabolic activity in CNS mediates this overgrowth effect.

MicroRNA-101 downregulates Alzheimer's amyloid-β precursor protein levels in human cell cultures and is differentially expressed.

The full repertoire of regulatory interactions utilized by human cells to control expression of amyloid-β precursor protein (APP) is still undefined. We investigated here the contribution of microRNA (miRNA) to this regulatory network. Several bioinformatic algorithms predicted miR-101 target sites within the APP 3'-untranslated region (3'-UTR).