Olfactory neuropathology in Alzheimer's disease: a sign of ongoing neurodegeneration.

Olfactory neuropathology is a cause of olfactory loss in Alzheimer's disease (AD). Olfactory dysfunction is also associated with memory and cognitive dysfunction and is an incidental finding of AD dementia. Here we review neuropathological research on the olfactory system in AD, considering both structural and functional evidence.

Astrocytic Regulation of Neural Circuits Underlying Behaviors.

Astrocytes, characterized by a satellite-like morphology, are the most abundant type of glia in the central nervous system. Their main functions have been thought to be limited to providing homeostatic support for neurons, but recent studies have revealed that astrocytes actually actively interact with local neural circuits and play a crucial role in information processing and generating physiological and behavioral responses. Here, we review the emerging roles of astrocytes in many brain regions, particularly by focusing on intracellular changes in astrocytes and their interactions with neurons at the molecular and neural circuit levels.

Multiplexed CRISPR-Cas9 system in a single adeno-associated virus to simultaneously knock out redundant clock genes.

The mammalian molecular clock is based on a transcription-translation feedback loop (TTFL) comprising the Period1, 2 (Per1, 2), Cryptochrome1, 2 (Cry1, 2), and Brain and Muscle ARNT-Like 1 (Bmal1) genes. The robustness of the TTFL is attributed to genetic redundancy among some essential clock genes, deterring genetic studies on molecular clocks using genome editing targeting single genes. To manipulate multiple clock genes in a streamlined and efficient manner, we developed a CRISPR-Cas9-based single adeno-associated viral (AAV) system targeting the circadian clock (CSAC) for essential clock genes including Pers, Crys, or Bmal1.

Region-specific amyloid-β accumulation in the olfactory system influences olfactory sensory neuronal dysfunction in 5xFAD mice.

Background: Hyposmia in Alzheimer's disease (AD) is a typical early symptom according to numerous previous clinical studies. Although amyloid-β (Aβ), which is one of the toxic factors upregulated early in AD, has been identified in many studies, even in the peripheral areas of the olfactory system, the pathology involving olfactory sensory neurons (OSNs) remains poorly understood.

Methods: Here, we focused on peripheral olfactory sensory neurons (OSNs) and delved deeper into the direct relationship between pathophysiological and behavioral results using odorants.

EEG Revealed That Fragrances Positively Affect Menopausal Symptoms in Mid-life Women.

During mid-life, women experienced not only physical but also neurological transition. Because of this, many women suffer from physiological and/or psychological menopausal symptoms. Although hormone therapy (HT) was broadly used to alleviate menopausal symptoms, HT showed inconsistent effects in case of psychological symptoms.

Odor habituation can modulate very early olfactory event-related potential.

Odor habituation is a phenomenon that after repeated exposure to an odor, is characterized by decreased responses to it. The central nervous system is involved in odor habituation. To study odor habituation in humans, measurement of event-related potentials (ERPs) has been widely used in the olfactory system and other sensory systems, because of their high temporal resolution.

Regulation of habenular G-protein gamma 8 on learning and memory via modulation of the central acetylcholine system.

Guanine nucleotide binding protein (G protein) gamma 8 (Gng8) is a subunit of G proteins and expressed in the medial habenula (MHb) and interpeduncular nucleus (IPN). Recent studies have demonstrated that Gng8 is involved in brain development; however, the roles of Gng8 on cognitive function have not yet been addressed. In the present study, we investigated the expression of Gng8 in the brain and found that Gng8 was predominantly expressed in the MHb-IPN circuit of the mouse brain.

Longitudinal profiling of oligomeric Aβ in human nasal discharge reflecting cognitive decline in probable Alzheimer's disease.

Despite clinical evidence indicating a close relationship between olfactory dysfunction and Alzheimer's disease (AD), further investigations are warranted to determine the diagnostic potential of nasal surrogate biomarkers for AD. In this study, we first identified soluble amyloid-β (Aβ), the key biomarker of AD, in patient nasal discharge using proteomic analysis. Then, we profiled the significant differences in Aβ oligomers level between patient groups with mild or moderate cognitive decline (n = 39) and an age-matched normal control group (n = 21) by immunoblot analysis and comparing the levels of Aβ by a self-standard method with interdigitated microelectrode sensor systems.

Timely Inhibitory Circuit Formation Controlled by Abl1 Regulates Innate Olfactory Behaviors in Mouse.

More than one-half of the interneurons in a mouse olfactory bulb (OB) develop during the first week after birth and predominantly connect to excitatory tufted cells near the superficial granule cell layer (sGCL), unlike late-born interneurons. However, the molecular mechanisms underlying the temporal specification are yet to be identified. In this study, we determined the role of Abelson tyrosine-protein kinase 1 (Abl1) in the temporal development of early-born OB interneurons.

Odor quality profile is partially influenced by verbal cues.

Characterizing an odor quality is difficult for humans. Ever-increasing physiological and behavioral studies have characterized odor quality and demonstrated high performance of human odor categorization. However, there are no precise methods for measuring the multidimensional axis of an odor quality.

Tanycytic TSPO inhibition induces lipophagy to regulate lipid metabolism and improve energy balance.

Unlabelled: Hypothalamic glial cells named tanycytes, which line the 3 ventricle (3V), are components of the hypothalamic network that regulates a diverse array of metabolic functions for energy homeostasis. Herein, we report that TSPO (translocator protein), an outer mitochondrial protein, is highly enriched in tanycytes and regulates homeostatic responses to nutrient excess as a potential target for an effective intervention in obesity. Administration of a TSPO ligand, PK11195, into the 3V, and tanycyte-specific deletion of reduced food intake and elevated energy expenditure, leading to negative energy balance in a high-fat diet challenge.

Spheroid Culture of Mammalian Olfactory Receptor Neurons: Potential Applications for a Bioelectronic Nose.

The olfactory system can detect many odorants with high sensitivity and selectivity based on the expression of nearly a thousand types of olfactory receptors (ORs) in olfactory receptor neurons (ORNs). These ORs have a dynamic odorant detection range and contribute to signal encoding processes in the olfactory bulb (OB). To harness the capabilities of the olfactory system and develop a biomimetic sensor, stable culture and maintenance of ORNs are required.

Regulation of Adipogenesis and Thermogenesis through Mouse Olfactory Receptor 23 Stimulated by α-Cedrene in 3T3-L1 Cells.

Olfactory receptors (ORs) are G protein-coupled receptors that perform important physiological functions beyond their role as odorant detectors in the olfactory sensory neurons. In the present study, we describe a novel role for one of these ORs, mouse olfactory receptor 23 (MOR23), as a regulator of adipogenesis and thermogenesis in 3T3-L1 cells. Downregulation of MOR23 by small interfering RNA in 3T3-L1 cells enhanced intracellular lipid accumulation and reduced the oxygen consumption rate.

Odorant Receptors Containing Conserved Amino Acid Sequences in Transmembrane Domain 7 Display Distinct Expression Patterns in Mammalian Tissues.

Mammalian genomes are well established, and highly conserved regions within odorant receptors that are unique from other G-protein coupled receptors have been identified. Numerous functional studies have focused on specific conserved amino acids motifs; however, not all conserved motifs have been sufficiently characterized. Here, we identified a highly conserved 18 amino acid sequence motif within transmembrane domain seven (CAS-TM7) which was identified by aligning odorant receptor sequences.

Distinct amyloid precursor protein processing machineries of the olfactory system.

Processing of amyloid precursor protein (APP) occurs through sequential cleavages first by β-secretase and then by the γ-secretase complex. However, abnormal processing of APP leads to excessive production of β-amyloid (Aβ) in the central nervous system (CNS), an event which is regarded as a primary cause of Alzheimer's disease (AD). In particular, gene mutations of the γ-secretase complex-which contains presenilin 1 or 2 as the catalytic core-could trigger marked Aβ accumulation.

Olfactory receptor 10J5 responding to α-cedrene regulates hepatic steatosis via the cAMP-PKA pathway.

Ectopic expression and functions of odorant receptors (ORs) in the human body have aroused much interest in the past decade. Mouse olfactory receptor 23 (MOR23, olfr16) and its human orthologue, OR10J5, have been found to be functionally expressed in several non-olfactory systems. Here, using MOR23- and OR10J5-expressing Hana3A cells, we identified α-cedrene, a natural compound that protects against hepatic steatosis in mice fed the high-fat diet, as a novel agonist of these receptors.

The erythropoietin-derived peptide MK-X and erythropoietin have neuroprotective effects against ischemic brain damage.

Erythropoietin (EPO) has been well known as a hematopoietic cytokine over the past decades. However, recent reports have demonstrated that EPO plays a neuroprotective role in the central nervous system, and EPO has been considered as a therapeutic target in neurodegenerative diseases such as ischemic stroke. Despite the neuroprotective effect of EPO, clinical trials have shown its unexpected side effects, including undesirable proliferative effects such as erythropoiesis and tumor growth.

Differential spatial expression of peripheral olfactory neuron-derived BACE1 induces olfactory impairment by region-specific accumulation of β-amyloid oligomer.

Olfactory dysfunction is a common symptom associated with neurodegenerative diseases including Alzheimer's disease (AD). Although evidence exists to suggest that peripheral olfactory organs are involved in the olfactory dysfunction that accompanies AD pathology, the underlying mechanisms are not fully understood. As confirmed using behavioral tests, transgenic mice overexpressing a Swedish mutant form of human amyloid precursor proteins exhibited olfactory impairments prior to evidence of cognitive impairment.