LRRC25 expression during physiological aging and in mouse models of Alzheimer's disease and iPSC-derived neurons.

The leucine-rich repeat-containing protein 25 (LRRC25) is relatively a novel protein with no information on its role in neuronal or brain function. A recent study suggested LRRC25 is a potential risk factor for Alzheimer's disease (AD). As a first step to understanding LRRC25's role in the brain and AD, we found LRRC25 is expressed in both cell membranes and cytoplasm in a punctuate appearance in astrocytes, microglia, and neurons in cell lines as well as mouse brain.

Identification of binding partners that facilitate membrane-type 5 matrix metalloproteinase (MT5-MMP) processing of amyloid precursor protein.

One of the pathological hallmarks of Alzheimer's disease (AD) is the presence of extracellular deposits of amyloid beta (Aβ) peptide. In addition to Aβ as the core component of the amyloid plaque, the amyloid precursor protein (APP) processing fragment Aβ was also found accumulated around the plaque. The APPη pathway, mainly mediated by membrane-type 5 matrix metalloproteinase (MT5-MMP), represents an important factor in AD pathogenesis.

Dementia exacerbates periodontal bone loss in females.

Background: Periodontitis is a chronic inflammatory disease defined by the pathologic loss of the periodontal ligament and alveolar bone in relation to aging. Although clinical cohort studies reported that periodontitis is significantly elevated in males compared to females, emerging evidence indicates that females with dementia are at a greater risk for periodontitis and decreased alveolar bone.

Objective: This study aimed to evaluate whether dementia is a potential sex-dependent risk factor for periodontal bone loss using an experimental model of periodontitis induced in the triple transgenic (3x-Tg) dementia-like mice and clinical samples collected from senior 65 plus age patients with diagnosed dementia.

Anti-inflammatory effects of CBD in human microglial cell line infected with HIV-1.

Human immunodeficiency virus (HIV) infection is associated with a chronic inflammatory stage and continuous activation of inflammasome pathway. We studied the anti-inflammatory effects of the compound cannabidiol (CBD) in comparison with Δ (9)-tetrahydrocannabinol [Δ(9)-THC] in human microglial cells (HC69.5) infected with HIV.

Novel Alzheimer risk factor IQ motif containing protein K is abundantly expressed in the brain and is markedly increased in patients with Alzheimer's disease.

Alzheimer's disease (AD) is complex and highly heterogeneous. Less than 10% of AD cases are early-onset (EOAD) caused by autosomal dominantly inherited mutations in amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 (PS2), each of which can increase Aβ generation and, thus, amyloid plaques. The remaining 90% of cases of AD are late-onset (LOAD) or sporadic.

Hyperactivity of Purkinje cell and motor deficits in C9orf72 knockout mice.

A hexanucleotide (GGGGCC) repeat expansion in the first intron of the C9ORF72 gene is the most frequently reported genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The cerebellum has not traditionally been thought to be involved in the pathogenesis of C9ORF72-associated ALS/FTD, but recent evidence suggested a potential role. C9ORF72 is highly expressed in the cerebellum.

TFEB protein expression is reduced in aged brains and its overexpression mitigates senescence-associated biomarkers and memory deficits in mice.

Identification of molecules and molecular pathways that can ameliorate aging-associated decline in cognitive function is crucial. Here we report that the protein levels of transcription factor EB (TFEB) were markedly reduced in both the cytosolic and nuclear fractions of the frontal cortex and hippocampus at 18-months of age relative to 6 months in the normal male wild-type mice. In the transgenic mice with ectopic expression of flag-TFEB in neurons, we observed that the levels of actin-normalized PGC1α and mtTFA were significantly increased in both the cortex and the hippocampus.

SARS-CoV-2 Infection in the Central and Peripheral Nervous System-Associated Morbidities and Their Potential Mechanism.

The recent outbreak of SARS-CoV-2 infections that causes coronavirus-induced disease of 2019 (COVID-19) is the defining and unprecedented global health crisis of our time in both the scale and magnitude. Although the respiratory tract is the primary target of SARS-CoV-2, accumulating evidence suggests that the virus may also invade both the central nervous system (CNS) and the peripheral nervous system (PNS) leading to numerous neurological issues including some serious complications such as seizures, encephalitis, and loss of consciousness. Here, we present a comprehensive review of the currently known role of SARS-CoV-2 and identify all the neurological problems reported among the COVID-19 case reports throughout the world.

Autophagy-Dependent Increased ADAM10 Mature Protein Induced by TFEB Overexpression Is Mediated Through PPARα.

Nonamyloidogenic processing of amyloid precursor protein (APP) by augmenting ADAM10 is a promising therapeutic strategy for Alzheimer's disease (AD). Therefore identification of molecular pathways that regulate ADAM10 expression is crucial. Autophagy is strongly dysregulated in AD, and TFEB was recently shown to be a master regulator of autophagy-lysosome pathway (ALP).

Potential Role of Phosphoglycerol Dihydroceramide Produced by Periodontal Pathogen in the Pathogenesis of Alzheimer's Disease.

Background: Among different types of sphingolipids produced by human cells, the possible engagement of ceramide species in the pathogenesis of Alzheimer's disease (AD) has attracted recent attention. While ceramides are primarily generated by synthesis in mammalian cells, only a limited number of bacterial species, produce ceramides, including phosphoglycerol dihydroceramide (PGDHC) that is produced by the key periodontal pathogen . Emerging evidence indicates that virulence factors produced by , such as lipopolysaccharide and gingipain, may be engaged in the initiation and/or progression of AD.

Nanoparticle-mediated approaches for Alzheimer's disease pathogenesis, diagnosis, and therapeutics.

Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder manifested by memory loss and cognitive impairment. Deposition of the amyloid β plaques has been identified as the most common AD pathology; however, the excessive accumulation of phosphorylated or total tau proteins, reactive oxygen species, and higher acetylcholinesterase activity are also strongly associated with Alzheimer's dementia. Several therapeutic approaches targeting these pathogenic mechanisms have failed in clinical or preclinical trials, partly due to the limited bioavailability, poor cell, and blood-brain barrier penetration, and low drug half-life of current regimens.

Correction: RanBP9 Overexpression Accelerates Loss of Pre and Postsynaptic Proteins in the APΔE9 Transgenic Mouse Brain.

[This corrects the article DOI: 10.1371/journal.pone.

TFEB-mediated Enhancement of the Autophagy-lysosomal Pathway Dually Modulates the Process of Amyloid β-Protein Generation in Neurons.

Abnormalities of the autophagy-lysosomal pathway (ALP) have been implicated in the pathology of Alzheimer's disease (AD). Activation of TFEB (transcription factor EB), a master regulator of the ALP, leads to ALP facilitation. The present study sought to clarify whether TFEB-mediated ALP facilitation influences the process of amyloid β-protein (Aβ) generation in neurons.

The neurotoxicity of amyloid β-protein oligomers is reversible in a primary neuron model.

Alzheimer's disease (AD) is characterized by the accumulation of extracellular amyloid β-protein (Aβ) and intracellular hyperphosphorylated tau proteins. Recent evidence suggests that soluble Aβ oligomers elicit neurotoxicity and synaptotoxicity, including tau abnormalities, and play an initiating role in the development of AD pathology. In this study, we focused on the unclarified issue of whether the neurotoxicity of Aβ oligomers is a reversible process.

Transcription Factor EB Is Selectively Reduced in the Nuclear Fractions of Alzheimer's and Amyotrophic Lateral Sclerosis Brains.

Multiple studies suggest that autophagy is strongly dysregulated in Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), as evidenced by accumulation of numerous autophagosomes, lysosomes with discontinuous membranes, and aggregated proteins in the patients' brains. Transcription factor EB (TFEB) was recently discovered to be a master regulator of lysosome biogenesis and autophagy. To examine whether aberrant autophagy in AD and ALS is due to alterations in TFEB expression, we systematically quantified the levels of TFEB in these brains by immunoblotting.

TFEB Overexpression in the P301S Model of Tauopathy Mitigates Increased PHF1 Levels and Lipofuscin Puncta and Rescues Memory Deficits.

Transcription factor EB (TFEB) was recently shown to be a master regulator of autophagy lysosome pathway. Here, we successfully generated and characterized transgenic mice overexpressing flag-TFEB. Enhanced autophagy in the flag-TFEB transgenic mice was confirmed by an increase in the cellular autophagy markers, as determined by both immunoblots and transmission electron microscopy.

LRP1 Downregulates the Alzheimer's β-Secretase BACE1 by Modulating Its Intraneuronal Trafficking.

The β-secretase called BACE1 is a membrane-associated protease that initiates the generation of amyloid β-protein (Aβ), a key event in Alzheimer's disease (AD). However, the mechanism of intraneuronal regulation of BACE1 is poorly understood. Here, we present evidence that low-density lipoprotein receptor-related protein 1 (LRP1), a multi-functional receptor, has a previously unrecognized function to regulate BACE1 in neurons.

A comparative evaluation of a novel vaccine in APP/PS1 mouse models of Alzheimer's disease.

Immunization against amyloid-beta-peptide (Aβ) has been widely investigated as a potential immunotherapeutic approach for Alzheimer's disease (AD). With the aim of developing an active immunogenic vaccine without need of coadjuvant modification for human trials and therefore avoiding such side effects, we designed the Aβ 1-42 vaccine (EB101), delivered in a liposomal matrix, that based on our previous studies significantly prevents and reverses the AD neuropathology, clearing Aβ plaques while markedly reducing neuronal degeneration, behavioral deficits, and minimizing neuroinflammation in APP/PS1 transgenic mice. Here, the efficacy of our immunogenic vaccine EB101 was compared with the original immunization vaccine cocktail Aβ 42 + CFA/IFA (Freund's adjuvant), in order to characterize the effect of sphingosine-1-phosphate (S1P) in the immunotherapeutic response.

COPS5 protein overexpression increases amyloid plaque burden, decreases spinophilin-immunoreactive puncta, and exacerbates learning and memory deficits in the mouse brain.

Brain accumulation of neurotoxic amyloid β (Aβ) peptide because of increased processing of amyloid precursor protein (APP), resulting in loss of synapses and neurodegeneration, is central to the pathogenesis of Alzheimer disease (AD). Therefore, the identification of molecules that regulate Aβ generation and those that cause synaptic damage is crucial for future therapeutic approaches for AD. We demonstrated previously that COPS5 regulates Aβ generation in neuronal cell lines in a RanBP9-dependent manner.

Substituted dithiazole piperazine benzamides as novel amyloid beta peptide reducing agents.

Alzheimer's disease is a persistent neurodegenerative disorder of elderly characterized clinically by irreversible loss of memory due to accumulation of amyloid beta peptides within the amyloid plaques. We report the parallel synthesis and screening results of diverse substituted di-thiazole piperazine benzamides. A new compound TPI-1917-49 was identified as a promising amyloid reducing agent by lowering the levels of Aβ at least in two cell types and in vivo.

RanBP9 overexpression accelerates loss of dendritic spines in a mouse model of Alzheimer's disease.

We previously demonstrated that RanBP9 overexpression increased Aβ generation and amyloid plaque burden, subsequently leading to robust reductions in the levels of several synaptic proteins as well as deficits in the learning and memory skills in a mouse model of Alzheimer's disease (AD). In the present study, we found striking reduction of spinophilin-immunoreactive puncta (52%, p<0.001) and spinophilin area (62.

AlphaLISA-based high-throughput screening assay to measure levels of soluble amyloid precursor protein α.

Activation of nonamyloidogenic processing of amyloid precursor protein (APP) has been hypothesized to be a viable approach for Alzheimer's disease drug discovery. However, until recently, the lack of HTS-compatible assay technologies precluded large scale screening efforts to discover molecules that potentiate nonamyloidogenic pathways. We have developed an HTS-compatible assay based on AlphaLISA technology that quantitatively detects soluble APPα (sAPPα), a marker of nonamyloidogenic processing of APP, released from live cells in low volume, 384-well plates.

An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo.

The phagocytosis of apoptotic cells (ACs), or efferocytosis, by DCs is critical for self-tolerance and host defense. Although many efferocytosis-associated receptors have been described in vitro, the functionality of these receptors in vivo has not been explored in depth. Using a spleen efferocytosis assay and targeted genetic deletion in mice, we identified a multiprotein complex--composed of the receptor tyrosine kinase AXL, LDL receptor-related protein-1 (LRP-1), and RAN-binding protein 9 (RANBP9)--that mediates DC efferocytosis and antigen cross-presentation.