Naomi Mamada

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, a key event in Alzheimer’s disease. However, the mechanism of inraneuronal regulation of BACE1 is poorly understood. Abstract 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. We show that deficiency of LRP1 exerts promotive effects on the protein expression and function of BACE1, whereas expression of LRP-L4, a functional LRP1 mini-receptor, specifically decreases BACE1 levels in both human embryonic kidney (HEK) 293 cells and rat primary neurons, leading to reduced Aβ production. Our subsequent analyses further demonstrate that (1) both endogenous and exogenous BACE1 and LRP1 interact with each other and are colocalized in soma and neurites of primary neurons, (2) LRP1 reduces the protein stability and cell-surface expression of BACE1, and (3) LRP1 facilitates the shift in intracellular localization of BACE1 from early to late endosomes, thereby promoting lysosomal degradation. These findings establish that LRP1 specifically downregulates BACE1 by modulating its intraneuronal trafficking and stability through protein interaction and highlight LRP1 as a potential therapeutic target in AD.

Mitochondria are devoid of amyloid β-protein (Aβ)-producing secretases: Evidence for unlikely occurrence within mitochondria of Aβ generation from amyloid precursor protein

Mitochondrial dysfunction is implicated in the pathological mechanism of Alzheimers disease (AD). Amyloid β-protein (Aβ), which plays a central role in AD pathogenesis, is reported to accumulate within mitochondria. However, a question remains as to whether Aβ is generated locally from amyloid precursor protein (APP) within mitochondria. We investigated this issue by analyzing the expression patterns of APP, APP-processing secretases, and APP metabolites in mitochondria separated from human neuroblastoma SH-SY5Y cells and those expressing Swedish mutant APP. APP, BACE1, and PEN-2 protein levels were significantly lower in crude mitochondria than microsome fractions while those of ADAM10 and the other γ-secretase complex components (presenilin 1, nicastrin, and APH-1) were comparable between fractions. The crude mitochondrial fraction containing substantial levels of cathepsin D, a lysosomal marker, was further separated via iodixanol gradient centrifugation to obtain mitochondria- and lysosome-enriched fractions. Mature APP, BACE1, and all γ-secretase complex components (in particular, presenilin 1 and PEN-2) were scarcely present in the mitochondria-enriched fraction, compared to the lysosome-enriched fraction. Moreover, expression of the β-C-terminal fragment (β-CTF) of APP was markedly low in the mitochondria-enriched fraction. Additionally, immunocytochemical analysis showed very little co-localization between presenilin 1 and Tom20, a marker protein of mitochondria. In view of the particularly low expression levels of BACE1, γ-secretase complex proteins, and β-CTF in mitochondria, we propose that it is unlikely that Aβ generation from APP occurs locally within this organelle.

Opsoclonus associated with autoantibodies to glutamate receptors δ2

Opsoclonus–myoclonus syndrome (OMS) is characterized by the onset of opsoclonus, myoclonus involving the trunk and limbs, and cerebellar ataxia. Opsoclonus, one of the key features of OMS, is a neurological disorder that causes horizontal sinusoidal oscillations without intersaccadic intervals. Although no autoantibody specific to opsoclonus has been found to date, opsoclonus does respond to immunotherapies, suggesting that an autoimmune mechanism may be involved in the development of opsoclonus [1]. We encountered a patient who developed opsoclonus and whose cerebrospinal fluid (CSF) was positive for antiglutamate receptor d2 (GluRd2) antibodies and in whom immunotherapy led to noticeable improvements in symptoms. Little is known about the association between opsoclonus and anti-GluRd2 antibodies. Only a few cases of anti-GluRd2 antibody-positive opsoclonus have been reported in the scientific literature, most of which have been published in Japan [2, 3]. The present case may provide important insight into the pathogenic mechanisms underlying opsoclonus. A 41-year-old woman presented with a primary complaint of dizziness. An upper respiratory infection for approximately 4 days was followed by the onset of dizziness. Two weeks after an antecedent infection, she developed left peripheral facial palsy. Ten weeks afterward, she developed tremors in her neck as well as in her legs when in a standing position. She presented with rapid, irregular, multidirectional eye movements (Video); minor left-sided facial palsy; and postural and action myoclonus in the head and neck area and in the limbs. Her deep tendon reflexes, including the mandibular reflex, were generally exaggerated. Orthostatic tremor was also observed, and she was unable to perform tandem gait. The peripheral blood count and biochemical blood parameters were within the normal range. A CSF examination revealed a normal protein level of 30 mg/dl and a slightly increased cell count of 10/ll (mononuclear cell count of 9/ ll and polymorphonuclear leukocyte count of 1/ll). The patient was positive for CSF oligoclonal bands, and she had an elevated IgG index of 1.35 (the normal value is below 0.73). Furthermore, her CSF was positive for anti-GluRd2 antibodies (measured by enzyme-linked immunosorbent assay) (the optical density level was increased in our patient (level [mean (SD) control value], d2-NT: 1.406 [0.413 (0.150)])). Anti-GluRe2 antibodies were also positive, and anti-GluR f1 antibodies were negative in CSF. A cranial MRI revealed no abnormalities. An electronystagmogram (ENG) showed opsoclonus (Fig. 1). The patient was diagnosed with OMS. From day 12 of hospitalization, the patient was treated with steroid pulse therapy (methylprednisolone, 1000 mg/day 9 3 days). As a result, although improvement in orthostatic tremor/myoclonus was observed, opsoclonus and myoclonus in the head and neck persisted. Intravenous immunoglobulin Electronic supplementary material The online version of this article (doi:10.1007/s10072-015-2264-4) contains supplementary material, which is available to authorized users.

Topographical disorientation in a patient with right parahippocampal infarction

We here describe a patient showing topographical disorientation (TD) after infarction of the right medial occipital lobe; the lesion included the parahippocampal gyrus. Clinical and neuropsychological observations demonstrated a specific pattern of impairment in terms of visual and visuospatial (topographical) learning, and memory. He had no landmark agnosia. His defective route finding resulted from impaired allocentric and egocentric spatial representations. Drawing illustrations of both familial and unfamiliar place and orientation tasks in an egocentric coordination context is a useful means of recognizing the influence of egocentric and/or allocentric spatial disturbance. The definition of “allocentric” or “egocentric” is confusing, and requires a standard for differentiating TD types.

Third nerve palsy due to local inflammation associated with vascular compression: A case series

Highlights • We report 2 cases of sudden-onset third nerve palsy due to vascular compression. • Both cases had risk factors for atherosclerosis. • Brain MRI revealed enhancement of the third nerve at the site of vascular compression. • Symptoms of third nerve palsy improved gradually without surgical intervention. • Inflammation superimposed on vascular compression can trigger third nerve palsy.