Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APP knock-in mouse model of Alzheimer's disease.

Introduction: Reduced brain energy metabolism, mammalian target of rapamycin (mTOR) dysregulation, and extracellular amyloid beta (Aβ) oligomer (xcAβO) buildup are some well-known Alzheimer's disease (AD) features; how they promote neurodegeneration is poorly understood. We previously reported that xcAβOs inhibit nutrient-induced mitochondrial activity (NiMA) in cultured neurons. We now report NiMA disruption in vivo.

Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APP knock-in mouse model of Alzheimer's disease.

Introduction: Reduced brain energy metabolism, mTOR dysregulation, and extracellular amyloid-β oligomer (xcAβO) buildup characterize AD; how they collectively promote neurodegeneration is poorly understood. We previously reported that xcAβOs inhibit N utrient-induced M itochondrial A ctivity (NiMA) in cultured neurons. We now report NiMA disruption .

Structural and functional damage to neuronal nuclei caused by extracellular tau oligomers.

Introduction: Neuronal nuclei are normally smoothly surfaced. In Alzheimer's disease (AD) and other tauopathies, though, they often develop invaginations. We investigated mechanisms and functional consequences of neuronal nuclear invagination in tauopathies.

Dysregulation of mTOR by tau in Alzheimer's disease.

Tau was discovered in the mid 1970's as a microtubule-associated protein that stimulates tubulin polymerization, and subsequently was shown to be expressed primarily in neurons, where it is most concentrated in axons. Interest in tau rose by the late 1980's, when it was shown to be the principal subunit of the neurofibrillary tangles (NFTs) that accumulate in Alzheimer's disease (AD) brain, and achieved new heights by the late 1990's, when numerous tau mutations were found to be highly penetrant for AD-related disorders that also are associated with NFTs and came to be known as non-Alzheimer's tauopathies. The role of tau in neurodegeneration is far more complex than whatever effects on neurons may be caused by NFTs, however, and here we review our work on dysregulation of mTOR by tau in AD.

Inceptor as a regulator of brain insulin sensitivity.

While historically viewed as an insulin insensitive organ, it is now accepted that insulin has a role in brain physiology. Changes in brain insulin and IGF1 signaling have been associated with neurological diseases, however the molecular factors regulating brain insulin sensitivity remain uncertain. In this study, we proposed that a recently described protein, termed Inceptor, may play a role in brain insulin and IGF1 resistance.

Structural and functional damage to neuronal nuclei caused by extracellular tau oligomers.

Introduction: Neuronal nuclei are normally smoothly surfaced. In Alzheimer's disease (AD) and other tauopathies, though, they often develop invaginations. We investigated mechanisms and functional consequences of neuronal nuclear invagination in tauopathies.

Extracellular Tau Oligomers Damage the Axon Initial Segment.

Background: In Alzheimer's disease (AD) brain, neuronal polarity and synaptic connectivity are compromised. A key structure for regulating polarity and functions of neurons is the axon initial segment (AIS), which segregates somatodendritic from axonal proteins and initiates action potentials. Toxic tau species, including extracellular oligomers (xcTauOs), spread tau pathology from neuron to neuron by a prion-like process, but few other cell biological effects of xcTauOs have been described.

Localization, induction, and cellular effects of tau phosphorylated at threonine 217.

Introduction: Tau phosphorylation at T217 is a promising Alzheimer's disease (AD) biomarker, but its functional consequences were unknown.

Methods: Human brain and cultured mouse neurons were analyzed by immunoblotting and immunofluorescence for total tau, tau , tau , tau , and tau . Direct stochastic optical reconstruction microscopy (dSTORM) super resolution microscopy was used to localize tau in cultured neurons.

High content screening miniaturization and single cell imaging of mature human feeder layer-free iPSC-derived neurons.

Human induced pluripotent stem cell (iPSC)-derived neurons are being increasingly used for high content imaging and screening. However, iPSC-derived neuronal differentiation and maturation is time-intensive, often requiring >8 weeks. Unfortunately, the differentiating and maturing iPSC-derived neuronal cultures also tend to migrate and coalesce into ganglion-like clusters making single-cell analysis challenging, especially in miniaturized formats.

Selective Detection of Misfolded Tau From Postmortem Alzheimer's Disease Brains.

Tau aggregates are present in multiple neurodegenerative diseases known as "tauopathies," including Alzheimer's disease, Pick's disease, progressive supranuclear palsy, and corticobasal degeneration. Such misfolded tau aggregates are therefore potential sources for selective detection and biomarker discovery. Six human tau isoforms present in brain tissues and both 3R and 4R isoforms have been observed in the neuronal inclusions.

SOD1 mediates lysosome-to-mitochondria communication and its dysregulation by amyloid-β oligomers.

Altered mitochondrial DNA (mtDNA) occurs in neurodegenerative disorders like Alzheimer's disease (AD); how mtDNA synthesis is linked to neurodegeneration is poorly understood. We previously discovered Nutrient-induced Mitochondrial Activity (NiMA), an inter-organelle signaling pathway where nutrient-stimulated lysosomal mTORC1 activity regulates mtDNA replication in neurons by a mechanism sensitive to amyloid-β oligomers (AβOs), a primary factor in AD pathogenesis (Norambuena et al., 2018).

Transcriptome and Translatome Regulation of Pathogenesis in Alzheimer's Disease Model Mice.

Background: Defining cellular mechanisms that drive Alzheimer's disease (AD) pathogenesis and progression will be aided by studies defining how gene expression patterns change during pre-symptomatic AD and ensuing periods of declining cognition. Previous studies have emphasized changes in transcriptome, but not translatome regulation, leaving the ultimate results of gene expression alterations relatively unexplored in the context of AD.

Objective: To identify genes whose expression might be regulated at the transcriptome and translatome levels in AD, we analyzed gene expression in cerebral cortex of two AD model mouse strains, CVN (APPSwDI;NOS2 -/- ) and Tg2576 (APPSw), and their companion wild type (WT) strains at 6 months of age by tandem RNA-Seq and Ribo-Seq (ribosome profiling).

A Novel Inhibitor Targeting NLRP3 Inflammasome Reduces Neuropathology and Improves Cognitive Function in Alzheimer's Disease Transgenic Mice.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and the most common type of dementia. A growing body of evidence has implicated neuroinflammation as an essential player in the etiology of AD. Inflammasomes are intracellular multiprotein complexes and essential components of innate immunity in response to pathogen- and danger-associated molecular patterns.

A three-dimensional dementia model reveals spontaneous cell cycle re-entry and a senescence-associated secretory phenotype.

A hexanucleotide repeat expansion on chromosome 9 open reading frame 72 (C9orf72) is associated with familial amyotrophic lateral sclerosis (ALS) and a subpopulation of patients with sporadic ALS and frontotemporal dementia. We used inducible pluripotent stem cells from neurotypic and C9orf72+ (C9+) ALS patients to derive neuronal progenitor cells. We demonstrated that C9+ and neurotypic neuronal progenitor cells differentiate into neurons.

Intraneuronal Tau Misfolding Induced by Extracellular Amyloid-β Oligomers.

Abnormal folding and aggregation of the microtubule-associated protein, tau, is a hallmark of several neurodegenerative disorders, including Alzheimer's disease (AD). Although normal tau is an intrinsically disordered protein, it does exhibit tertiary structure whereby the N- and C-termini are often in close proximity to each other and to the contiguous microtubule-binding repeat domains that extend C-terminally from the middle of the protein. Unfolding of this paperclip-like conformation might precede formation of toxic tau oligomers and filaments, like those found in AD brain.

The Promise and Perils of Compound Discovery Screening with Inducible Pluripotent Cell-Derived Neurons.

Neurological diseases comprise more than a thousand ailments that adversely affect the brain and nervous system. When grouped together, these neurological conditions impact an estimated 100 million individuals in the United States and up to a billion people worldwide, making drug discovery efforts imperative. However, recent research and development efforts for these neurological diseases, including Alzheimer's disease and amyotrophic lateral sclerosis, have been exceedingly disappointing and typify the challenges associated with translating and cell-based discoveries to successful preclinical models and subsequent human clinical trials.

Aberrant Neuronal Cell Cycle Re-Entry: The Pathological Confluence of Alzheimer's Disease and Brain Insulin Resistance, and Its Relation to Cancer.

Aberrant neuronal cell cycle re-entry (CCR) is a phenomenon that precedes and may mechanistically lead to a majority of the neuronal loss observed in Alzheimer's disease (AD). Recent developments concerning the regulation of aberrant neuronal CCR in AD suggest that there are potential intracellular signaling "hotspots" in AD, cancer, and brain insulin resistance, the latter of which is characteristically associated with AD. Critically, these common signaling nodes across different human diseases may represent currently untapped therapeutic opportunities for AD.

A novel lysosome-to-mitochondria signaling pathway disrupted by amyloid-β oligomers.

The mechanisms of mitochondrial dysfunction in Alzheimer's disease are incompletely understood. Using two-photon fluorescence lifetime microscopy of the coenzymes, NADH and NADPH, and tracking brain oxygen metabolism with multi-parametric photoacoustic microscopy, we show that activation of lysosomal mechanistic target of rapamycin complex 1 (mTORC1) by insulin or amino acids stimulates mitochondrial activity and regulates mitochondrial DNA synthesis in neurons. Amyloid-β oligomers, which are precursors of amyloid plaques in Alzheimer's disease brain and stimulate mTORC1 protein kinase activity at the plasma membrane but not at lysosomes, block this Nutrient-induced Mitochondrial Activity (NiMA) by a mechanism dependent on tau, which forms neurofibrillary tangles in Alzheimer's disease brain.

N-methyl-D-aspartate receptor-mediated calcium influx connects amyloid-β oligomers to ectopic neuronal cell cycle reentry in Alzheimer's disease.

Introduction: Alzheimer's disease (AD) symptoms reflect synaptic dysfunction and neuron death. Amyloid-β oligomers (AβOs) induce excess calcium entry into neurons via N-methyl-D-aspartate receptors (NMDARs), contributing to synaptic dysfunction. The study described here tested the hypothesis that AβO-stimulated calcium entry also drives neuronal cell cycle reentry (CCR), a prelude to neuron death in AD.

Bidirectional modulation of Alzheimer phenotype by alpha-synuclein in mice and primary neurons.

α-Synuclein (αSyn) histopathology defines several neurodegenerative disorders, including Parkinson's disease, Lewy body dementia, and Alzheimer's disease (AD). However, the functional link between soluble αSyn and disease etiology remains elusive, especially in AD. We, therefore, genetically targeted αSyn in APP transgenic mice modeling AD and mouse primary neurons.

Reduced brain insulin signaling: A seminal process in Alzheimer's disease pathogenesis.

The synaptic dysfunction and death of neurons that mediate memory and cognition account together for the behavioral symptoms of Alzheimer's disease (AD). Reduced insulin signaling in the brain is a hallmark of AD patients, even in the absence of systemic type 1 or type 2 diabetes, prompting some researchers to refer to AD as brain-specific, or type 3 diabetes. A key question that arises about this signature feature of AD is "how, if at all, does the brain's impaired ability to utilize insulin contribute to the behavioral deficits associated with AD?" The fact that type 2 diabetes is a risk factor for AD suggests a causative role for impaired insulin responsiveness in AD pathogenesis, but how that might occur at a detailed molecular level had been elusive.

Extracellular Tau Oligomers Induce Invasion of Endogenous Tau into the Somatodendritic Compartment and Axonal Transport Dysfunction.

Aggregates composed of the microtubule associated protein, tau, are a hallmark of Alzheimer's disease and non-Alzheimer's tauopathies. Extracellular tau can induce the accumulation and aggregation of intracellular tau, and tau pathology can be transmitted along neural networks over time. There are six splice variants of central nervous system tau, and various oligomeric and fibrillar forms are associated with neurodegeneration in vivo.