Contribution of amyloid deposition from oligodendrocytes in a mouse model of Alzheimer's disease.

Background: The accumulation of β-amyloid (Aβ) peptides into insoluble plaques is an early pathological feature of Alzheimer's disease (AD). BACE1 is the sole β-secretase for Aβ generation, making it an attractive therapeutic target for AD therapy. While BACE1 inhibitors have been shown to reduce Aβ levels in people with AD, clinical trials targeting BACE1 have failed due to unwanted synaptic deficits.

Ex vivo propagation of synaptically-evoked cortical depolarizations in a mouse model of Alzheimer's disease at 20 Hz, 40 Hz, or 83 Hz.

Sensory stimulations at 40 Hz gamma (but not any other frequency), have shown promise in reversing Alzheimer's disease (AD)-related pathologies. What distinguishes 40 Hz? We hypothesized that stimuli at 40 Hz might summate more efficiently (temporal summation) or propagate more efficiently between cortical layers (vertically), or along cortical laminas (horizontally), compared to inputs at 20 or 83 Hz. To investigate these hypotheses, we used brain slices from AD mouse model animals (5xFAD).

Oligodendrocytes produce amyloid-β and contribute to plaque formation alongside neurons in Alzheimer's disease model mice.

Amyloid-β (Aβ) is thought to be neuronally derived in Alzheimer's disease (AD). However, transcripts of amyloid precursor protein (APP) and amyloidogenic enzymes are equally abundant in oligodendrocytes (OLs). By cell-type-specific deletion of Bace1 in a humanized knock-in AD model, APP, we demonstrate that OLs and neurons contribute to Aβ plaque burden.

Increased gene dosage of RFWD2 causes autistic-like behaviors and aberrant synaptic formation and function in mice.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions, communication deficits and repetitive behaviors. A study of autistic human subjects has identified RFWD2 as a susceptibility gene for autism, and autistic patients have 3 copies of the RFWD2 gene. The role of RFWD2 as an E3 ligase in neuronal functions, and its contribution to the pathophysiology of ASD, remain unknown.

ER-stress response in retinal Müller glia occurs significantly earlier than amyloid pathology in the Alzheimer's mouse brain and retina.

Alzheimer's Disease (AD) pathogenesis is thought to begin up to 20 years before cognitive symptoms appear, suggesting the need for more sensitive diagnostic biomarkers of AD. In this report, we demonstrated pathological changes in retinal Müller glia significantly earlier than amyloid pathology in AD mouse models. By utilizing the knock-in NLGF mouse model, we surprisingly discovered an increase in reticulon 3 (RTN3) protein levels in the NLGF retina as early as postnatal day 30 (P30).

Accumulation of neutral lipids in dystrophic neurites surrounding amyloid plaques in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the formation β-amyloid (Aβ) deposited neuritic plaques. Recent evidence suggests that abnormal lipid metabolism and accumulation could serve as biomarkers for neurodegenerative diseases, including AD. Tubular endoplasmic reticulum protein, reticulon 3 (RTN3), plays a crucial role in the development of neuritic plaque and lipid metabolism in AD brains.

Loss of Endothelial TDP-43 Leads to Blood Brain Barrier Defects in Mouse Models of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.

Loss of nuclear TDP-43 occurs in a wide range of neurodegenerative diseases, and specific mutations in the gene that encodes the protein are linked to familial Frontal Temporal Lobar Dementia (FTD), and Amyotrophic Lateral Sclerosis (ALS). Although the focus has been on neuronal cell dysfunction caused by TDP-43 variants, mRNA transcripts are expressed at similar levels in brain endothelial cells (ECs). Since increased permeability across the blood brain barrier (BBB) precedes cognitive decline, we postulated that altered functions of TDP-43 in ECs contributes to BBB dysfunction in neurodegenerative disease.

Bace1 Deletion in the Adult Reverses Epileptiform Activity and Sleep-wake Disturbances in AD Mice.

Alzheimer's disease (AD) increases the risk for seizures and sleep disorders. We show here that germline deletion of β-site amyloid precursor protein (APP) cleaving enzyme-1 (BACE1) in neurons, but not in astrocytes, increased epileptiform activity. However, deletion at adult ages did not alter the normal EEG waveform, indicating less concern for BACE1 inhibition in patients.

Reticulons 1 and 3 are essential for axonal growth and synaptic maintenance associated with intellectual development.

Reticulon (RTN) proteins are a family of proteins biochemically identified for shaping tubular endoplasmic reticulum, a subcellular structure important for vesicular transport and cell-to-cell communication. In our recent study of mice with knockout of both reticulon 1 (Rtn1) and Rtn3, we discovered that Rtn1-/-;Rtn3-/- (brief as R1R3dKO) mice exhibited neonatal lethality, despite the fact that mice deficient in either RTN1 or RTN3 alone exhibit no discernible phenotypes. This has been the first case to find early lethality in animals with deletion of partial members of RTN proteins.

BACE1 regulates expression of Clusterin in astrocytes for enhancing clearance of β-amyloid peptides.

Background: Abnormal accumulation of amyloid beta peptide (Aβ) in the brain induces a cascade of pathological changes in Alzheimer's disease (AD), and inhibiting BACE1, which is required for Aβ generation, is therefore being explored for the treatment of AD by reducing Aβ accumulation. As Bace1 knockout mice exhibit increased number of reactive astrocytes and AD brains have reactive astrocytes that surround amyloid plaques, we investigated the role of BACE1 in astrocytes and determined whether BACE1 regulates astrocytic functions.

Methods: We conducted unbiased single cell RNA-seq (scRNA-seq) using purified astrocytes from Bace1 KO mice and wild type control littermates.

Klotho Regulated by Estrogen Plays a Key Role in Sex Differences in Stress Resilience in Rats.

Klotho (KL) is a glycosyl hydrolase and aging-suppressor gene. Stress is a risk factor for depression and anxiety, which are highly comorbid with each other. The aim of this study is to determine whether KL is regulated by estrogen and plays an important role in sex differences in stress resilience.

Postnatal neuronal Bace1 deletion impairs neuroblast and oligodendrocyte maturation.

Beta amyloid cleaving enzyme 1 (BACE1) is largely expressed by neurons and is the sole β-secretase for initiating the production of neuronal β-amyloid peptides (Aβ). To fully understand the physiological functions of neuronal BACE1, we used mouse genetic approach coupled with unbiased single nucleus RNA sequencing (snRNAseq) to investigate how targeted deletion of Bace1 in neurons, driven by Thy-1-Cre recombinase, would affect functions in the nervous system. Our transcriptome results revealed that BACE1 is essential for maturation of neural precursor cells and oligodendrocytes in mice.

The CX3CL1 intracellular domain exhibits neuroprotection via insulin receptor/insulin-like growth factor receptor signaling.

CX3CL1, also known as fractalkine, is best known for its signaling activity through interactions with its cognate receptor CX3CR1. However, its intrinsic function that is independent of interaction with CX3CR1 remains to be fully understood. We demonstrate that the intracellular domain of CX3CL1 (CX3CL1-ICD), generated upon sequential cleavages by α-/β-secretase and γ-secretase, initiates a back signaling activity, which mediates direct signal transmission to gene expression in the nucleus.

Targeted BACE-1 inhibition in microglia enhances amyloid clearance and improved cognitive performance.

Abnormal accumulation of β-amyloid (Aβ) peptides is a culprit in Alzheimer's disease (AD); blocking Aβ generation is therefore being explored as a logical approach for AD treatment. Here, we demonstrate that targeted inhibition of β-site amyloid precursor protein (APP) cleaving enzyme-1 (BACE-1) in microglia has unique advantages. When was deleted in Alzheimer's 5xFAD microglia, fewer amyloid plaques developed, and this reduction was not due to changes in APP processing but rather to enhanced Aβ clearance, in line with the increase in a microglial gene signature favoring phagocytosis.

Evoked Cortical Depolarizations Before and After the Amyloid Plaque Accumulation: Voltage Imaging Study.

Background: In Alzheimer's disease (AD), synaptic dysfunction is thought to occur many years before the onset of cognitive decline.

Objective: Detecting synaptic dysfunctions at the earliest stage of AD would be desirable in both clinic and research settings.

Methods: Population voltage imaging allows monitoring of synaptic depolarizations, to which calcium imaging is relatively blind.

BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1.

BACE-1 is required for generating β-amyloid (Aβ) peptides in Alzheimer's disease (AD). Here, we report that microglial BACE-1 regulates the transition of homeostatic to stage 1 disease-associated microglia (DAM-1) signature. BACE-1 deficiency elevated levels of transcription factors including , , , , , , and in the transition signature, which transition from more homeostatic to highly phagocytic DAM-1.

Loss of RTN3 phenocopies chronic kidney disease and results in activation of the IGF2-JAK2 pathway in proximal tubular epithelial cells.

Reticulon 3 (RTN3) is an endoplasmic reticulum protein that has previously been shown to play roles in neurodegenerative diseases, but little is known about its function in the kidneys. The aim of the present study was to clarify the roles of RTN3 in chronic kidney disease (CKD) and kidney fibrosis. In this study, RTN3 levels were measured in kidney tissues from healthy controls and CKD or kidney fibrosis patients.

Alzheimer's disease amyloidogenesis is linked to altered lower urinary tract physiology.

Aims: While most Alzheimer's disease (AD) research emphasizes cognitive and behavioral abnormalities, lower urinary tract symptoms (LUTS) are observed in a third of AD patients, contributing to morbidity, poor quality of life, and need for institutionalization. Alzheimer's disease-associated urinary dysfunction (ADUD) has been assumed to be due to cognitive decline alone. While mouse studies have suggested that bladder innervation and voiding behavior may be altered in AD models, technical challenges precluded voiding reflex assessments.

Distinct profiles of cellular senescence-associated gene expression in the aged, diseased or injured central nervous system.

The molecular process of cellular senescence, which is known to contribute to aging, has been implicated in several diseases of the central nervous system (CNS). The purpose of this study was to generate an unbiased survey of cellular senescence gene expression with whole brain tissues using a standardized, curated set of 88 genes associated with cellular senescence. We performed a comparative analysis of aged brains with two CNS disease models; the 5xFAD mouse model of Alzheimer's disease, and cuprizone-induced CNS demyelination.

Regulatory role of cathepsin L in induction of nuclear laminopathy in Alzheimer's disease.

Experimental and clinical therapies in the field of Alzheimer's disease (AD) have focused on elimination of extracellular amyloid beta aggregates or prevention of cytoplasmic neuronal fibrillary tangles formation, yet these approaches have been generally ineffective. Interruption of nuclear lamina integrity, or laminopathy, is a newly identified concept in AD pathophysiology. Unraveling the molecular players in the induction of nuclear lamina damage may lead to identification of new therapies.

The case for low-level BACE1 inhibition for the prevention of Alzheimer disease.

Alzheimer disease (AD) is the most common cause of dementia in older individuals (>65 years) and has a long presymptomatic phase. Preventive therapies for AD are not yet available, and potential disease-modifying therapies targeting amyloid-β plaques in symptomatic stages of AD have only just been approved in the United States. Small-molecule inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1; also known as β-secretase 1) reduce the production of amyloid-β peptide and are among the most advanced drug candidates for AD.