Ai Hosaka

Neuronal β-amyloid generation is independent of lipid raft association of β-secretase BACE1: analysis with a palmitoylation-deficient mutant

β‐Secretase, BACE1 is a neuron‐specific membrane‐associated protease that cleaves amyloid precursor protein (APP) to generate β‐amyloid protein (Aβ). BACE1 is partially localized in lipid rafts. We investigated whether lipid raft localization of BACE1 affects Aβ production in neurons using a palmitoylation‐deficient mutant and further analyzed the relationship between palmitoylation of BACE1 and its shedding and dimerization. We initially confirmed that BACE1 is mainly palmitoylated at four C‐terminal cysteine residues in stably transfected neuroblastoma cells. We found that raft localization of mutant BACE1 lacking the palmitoylation modification was markedly reduced in comparison to wild‐type BACE1 in neuroblastoma cells as well as rat primary cortical neurons expressing BACE1 via recombinant adenoviruses. In primary neurons, expression of wild‐type and mutant BACE1 enhanced production of Aβ from endogenous or overexpressed APP to similar extents with the β‐C‐terminal fragment (β‐CTF) of APP mainly distributed in nonraft fractions. Similarly, β‐CTF was recovered mainly in nonraft fractions of neurons expressing Swedish mutant APP only. These results show that raft association of BACE1 does not influence β‐cleavage of APP and Aβ production in neurons, and support the view that BACE1 cleaves APP mainly in nonraft domains. Thus, we propose a model of neuronal Aβ generation involving mobilization of β‐CTF from nonraft to raft domains. Additionally, we obtained data indicating that palmitoylation plays a role in BACE1 shedding but not dimerization.

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.

Magnetic resonance images of herpes zoster myelitis presenting with Brown-Séquard syndrome.

A 32-YEAR-OLD RIGHThanded woman was febrile at 39°C for 3 consecutive days, after which she developed a rash accompanied by blisters on the lips and nasal cavity and an abnormal sensation in the peripheral parts of the right lower extremity. Eight days after the onset of neurological abnormalities, the salient neurological features were diminished sensation to pain and temperature on the right side below the T4 dermatome; diminished sensation to pain, temperature, and touch on the left side of the T3 dermatome; loss of touch sensibility on the left side below the T4 dermatome; and incomplete paresis of the left leg. Based on these neurological findings, she was diagnosed with Brown-Séquard syndrome. Magnetic resonance imaging showed a left-dominant, highsignal lesion (Figure 1, A and B) or a gadolinium-enhanced lesion on the left side (Figure 2, A and B) in the spine, particularly at the first and second thoracic vertebrae. Although results of cerebrospinal fluid testing showed that both the cell count and protein level were within the reference range, it revealed Human herpesvirus 3 (varicella-zoster virus) DNA in the spinal fluid using polymerase chain reaction, leading to the diagnosis of herpes zoster myelitis. Combined therapy with steroid pulse and intravenous acyclovir was performed. After 1 week, muscle power of her left iliopsoas and quadriceps increased from 3 and 4 to 5 and 5, respectively, according to manual muscle testing, and she could walk independently without the aid of a stick. After 1 month, bilateral abnormal sensation levels moved down to the T6 dermatome, and the appearance of the lesion on magnetic resonance imaging was reduced. Sensory dissociation, left hyperreflexia, and left positive Babinski signs remained after 3 months. Throughout the course of her disease, no abnormalities in bladder control or deep sensation (eg, position and vibration) were observed.

Organizing Pneumonia as the First Clinical Manifestation of Early Stage Rheumatoid Arthritis Determined by Hand Joints Synovitis Using Magnetic Resonance Imaging

We report the case of a 50-year-old man who presented with organizing pneumonia (OP) as the first manifestation of rheumatoid arthritis (RA). He experienced repeated episodes of pneumonia, which did not respond to several antibiotics. The lymphocyte dominant cell increase in the bronchoalveolar lavage fluid on chest computerized tomography suggested OP. Although he did not present with articular symptoms, magnetic resonance imaging (MRI) revealed synovitis of the hand joints without joint erosion, suggesting that this was a case of early stage RA. The MRI may be a useful diagnostic tool in asymptomatic patients with early stage RA.

Intravascular large B cell lymphoma with neurological symptoms diagnosed on the basis of a senile angioma-like eruption

Intravascular large B cell lymphoma (IVLBCL) presents various neurological symptoms, and the prognosis frequently deteriorates with a delay in diagnosis. In addition, for the diagnosis of IVLBCL, invasive biopsies are generally performed in main organs, such as the brain. We report a case of IVLBCL in which an early diagnosis was enabled by skin biopsy. The patient in this case had cauda equine syndrome and had developed multiple brain infarctions. She received six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) treatment and is currently in complete remission. At the macroscopic level, her lesions resembled senile angioma, commonly observed in normal elderly persons. Eruptions of this type are not currently recognised as IVLBCL lesions and might easily be overlooked. In cases in which IVLBCL could be suspected, an active search and biopsy of skin lesions, including an eruption of this type, are useful for early diagnosis and treatment.

GCH1 mutations in dopa-responsive dystonia and Parkinson’s disease

Guanosine triphosphate cyclohydrolase I (GCH1) mutations are associated with increased risk for dopa-responsive dystonia (DRD) and Parkinson’s disease (PD). Herein, we investigated the frequency of GCH1 mutations and clinical symptoms in patients with clinically diagnosed PD and DRD. We used the Sanger method to screen entire exons in 268 patients with PD and 26 patients with DRD, with the examinations of brain magnetic resonance imaging scans, striatal dopamine transporter scans, and [123I] metaiodobenzylguanidine (MIBG) myocardiac scintigraphy scans. We identified 15 patients with heterozygous GCH1 mutations from seven probands and five sporadic cases. The prevalence of GCH1 mutations in probands was different between PD [1.9% (5/268)] and DRD [26.9% (7/26)] (p value < 0.0001). The onset age tends to be different between PD and DRD patients: 35.4 ± 25.3 and 16.5 ± 13.6, respectively (average ± SD; p = 0.08). Most of the patients were women (14/15). Dystonia was common symptom, and dysautonomia and cognitive decline were uncommon in our PD and DRD. All patients presented mild parkinsonism or dystonia with excellent response to levodopa. Seven of seven DRD and three of five PD presented normal heart-to-mediastinum ratio on MIBG myocardial scintigraphy. Five of six DRD and three of four PD demonstrated normal densities of dopamine transporter. Our findings elucidated the clinical characteristics of PD and DRD patients due to GCH1 mutations. PD patients with GCH1 mutations also had different symptoms from those seen in typical PD. The patients with GCH1 mutations had heterogeneous clinical symptoms.

The first case of POEMS syndrome with synchronous breast cancer: What are the associated diagnostic challenges?

Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, Skin changes (POEMS) syndrome is a rare plasma cell disorder that causes a paraneoplastic syndrome. We report the first case of POEMS syndrome with synchronous breast cancer. The patient was at risk of being misdiagnosed with metastatic cancer, and it is important to emphasize that physical examinations provided vital diagnostic clues.

Cerebral Venous Air Embolism due to a Hidden Skull Fracture Secondary to Head Trauma.

Cerebral venous air embolism is sometimes caused by head trauma. One of the paths of air entry is considered a skull fracture. We report a case of cerebral venous air embolism following head trauma. The patient was a 55-year-old man who fell and hit his head. A head computed tomography (CT) scan showed the air in the superior sagittal sinus; however, no skull fractures were detected. Follow-up CT revealed a fracture line in the right temporal bone. Cerebral venous air embolism following head trauma might have occult skull fractures even if CT could not show the skull fractures.

Biochemical analysis of wild-type Bri peptides in plasma obtained from non-FBD subjects

P4-173 PRION DISEASE MASQUERADING AS ALZHEIMER’S DISEASE Andrew Thompson, Colin Mahoney, Natalie Ryan, Nin Bajaj, Ana Lukic, Chris Carswell, Harpreet Hyare, Gosala Gopalakrishnan, Cath Mummery, John Collinge, Peter Rudge, Nick Fox, Simon Mead, National Prion Clinic, London, United Kingdom; Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom; Institute of Neuroscience, Nottingham, United Kingdom; MRC Prion Unit, London, United Kingdom.

A case of idiopathic hypertrophic cranial pachymeningitis presenting high values of matrix metalloproteinase

This report concerns a 53-year-old male patient with idiopathic hypertrophic cranial pachymeningitis who presented with multiple cranial nerve palsies (I, II, III, IV, V, VI). Brain magnetic resonance imaging showed diffuse thickening and gadolinium enhancement of the cerebral dura mater. A biopsy of the cerebral dura mater showed granulomatous vasculitis with histiocyte infiltration. Although both the serum rheumatoid factor (RF) and matrix metalloproteinase-3 (MMP-3) were high, the patient showed no signs of arthritis. He was anti-cyclic citrullinated peptide antibody negative, which makes the presence of comorbid chronic rheumatoid arthritis (RA) unlikely. The aetiology of the pachymeningitis was unknown, which led to the diagnosis of idiopathic hypertrophic cranial pachymeningitis. Steroid pulse therapy successfully diminished the patient’s pachymeningitis and lowered both RF and MMP-3. High values of RF suggest the possible involvement of an autoimmune mechanism, and the MMP value may be an important indicator of the aetiology of pachymeningitis with granulomatous vasculitis.