Novel aspects of the phosphorylation and structure of pathological tau: implications for tauopathy biomarkers.

The deposition of highly phosphorylated and aggregated tau is a characteristic of tauopathies, including Alzheimer's disease. It has long been known that different isoforms of tau are aggregated in different cell types and brain regions in each tauopathy. Recent advances in analytical techniques revealed the details of the biochemical and structural biological differences of tau specific to each tauopathy. In this review, we explain recent advances in the analysis of post-translational modifications of tau, particularly phosphorylation, brought about by the development of mass-spectrometry and Phos-tag technology. We then discuss the structure of tau filaments in each tauopathy revealed by the advent of cryo-EM. Finally, we describe the progress in biofluid and imaging biomarkers for tauopathy. This review summarizes current efforts to elucidate the characteristics of pathological tau and the landscape of the use of tau as a biomarker to diagnose and determine the pathological stage of tauopathy.

INPP5D modulates TREM2 loss-of-function phenotypes in a ß-amyloidosis mouse model.

The genetic associations of TREM2 loss-of-function variants with Alzheimer disease (AD) indicate the protective roles of microglia in AD pathogenesis. Functional deficiencies of TREM2 disrupt microglial clustering around amyloid ß (Aß) plaques, impair their transcriptional response to Aß, and worsen neuritic dystrophy. However, the molecular mechanism underlying these phenotypes remains unclear. In this study, we investigated the pathological role of another AD risk gene, INPP5D, encoding a phosphoinositide PI(3,4,5)P3 phosphatase expressed in microglia. In a Tyrobp-deficient TREM2 loss-of-function mouse model, Inpp5d haplodeficiency restored the association of microglia with Aß plaques, partially restored plaque compaction, and astrogliosis, and reduced phosphorylated tau+ dystrophic neurites. Mechanistic analyses suggest that TREM2/TYROBP and INPP5D exert opposing effects on PI(3,4,5)P3 signaling pathways as well as on phosphoproteins involved in the actin assembly. Our results suggest that INPP5D acts downstream of TREM2/TYROBP to regulate the microglial barrier against Aß toxicity, thereby modulates Aß-dependent pathological conversion of tau.

Soluble form of the APP fragment, sAPPß, positively regulates tau secretion.

Extracellular tau has been highlighted in the pathogenesis of Alzheimer disease (AD), which is the most common neurodegenerative disease. Pathological analyses as well as model animal studies suggest that amyloid-ß peptide (Aß) deposition facilitates the spreading of tau aggregation pathology via extracellular tau. However, the precise mechanism of tau secretion remains unknown. Here, we show that the overexpression of amyloid precursor protein (APP) enhances the secretion of tau phosphorylated at threonine 181 in mouse neuroblastoma Neuro2a cells. Moreover, we found that soluble amyloid precursor protein ß (sAPPß), which is generated by ß-site APP cleaving enzyme 1 (BACE1), mediates tau secretion. Our results demonstrate that BACE1-mediated cleavage of APP plays pathological roles in AD pathogenesis by not only Aß production, but by the spreading of tau aggregation pathology via sAPPß in AD patients.

Identification of calcium and integrin-binding protein 1 as a novel regulator of production of amyloid ß peptide using CRISPR/Cas9-based screening system.

The aberrant metabolism of amyloid ß peptide (Aß) has been implicated in the etiology of Alzheimer disease (AD). Aß is produced via the sequential cleavage of amyloid precursor protein (APP) by ß- and γ-secretases. However, the precise regulatory mechanism of Aß generation still remains unclear. To gain a better understanding of the molecular mechanism of Aß production, we established a genetic screening method based on the CRISPR/Cas9 system to identify novel regulators of Aß production. We successfully identified calcium and integrin-binding protein 1 (CIB1) as a potential negative regulator of Aß production. The disruption of Cib1 significantly upregulated Aß levels. In addition, immunoprecipitation experiments demonstrated that CIB1 interacts with the γ-secretase complex. Moreover, the disruption of Cib1 specifically reduced the cell-surface localization of mature Nicastrin (Nct), which is a component of the γ-secretase complex, without changing the intrinsic activity of γ-secretase. Finally, we confirmed using the single-cell RNA-seq data in human that CIB1 mRNA level in neuron was decreased in the early stage of AD. Taken together, our results indicate that CIB1 regulates Aß production via controlling the subcellular localization of γ-secretase, suggesting CIB1 is involved in the development of AD.

A Case of Orbital Xanthogranuloma Treated by Surgical Excision.

Orbital xanthogranuloma is an uncommon tumor. It is usually associated with a systemic or hematological disease. This report presents a rare case of orbital xanthogranuloma associated with heart disease and thrombocytopenia. A 52-year-old female presented with a bilateral periorbital subcutaneous tumor that had existed for 3 years. Although immunoglobulin levels were within the normal limits, thrombocytopenia, slight anemia and increased levels of C-reactive protein and alkaline phosphatase were observed. The mass was excised successfully. The malar flap elevation technique made it easy to approach the periorbital subcutaneous mass. A histopathological study led to a diagnosis of xanthogranuloma based on the presence of infiltration of histiocytes and Touton-type giant cells.

Conservative surgical treatment for early-stage vulvar malignant melanoma.

PURPOSE: To investigate the efficacy of wide local excision as a surgical treatment for early-stage vulvar melanomas. METHODS: Wide local excision with or without lymph node dissection was performed in three patients with stage I vulvar melanoma (American Joint Committee on Cancer classification, 1992). RESULTS: All three patients were successfully treated by wide local excision. There was no evidence of recurrence at long-term follow-up in any of the patients. CONCLUSIONS: Wide local excision with adequate tumor-free margins should be considered the treatment of choice for early-stage vulvar melanomas.

Sural perforator flap: assessment of the posterior calf region as donor site for a free fasciocutaneous flap.

Three kinds of free fasciocutaneous flap from the posterior calf region have been described in the literature: the medial sural perforator flap, the lateral sural perforator flap, and the traditional posterior calf fasciocutaneous flap that is supplied by superficial cutaneous vessels. Moreover, it has been reported that superficial cutaneous vessels are of a suitable size for microanastomosis when deep musculocutaneous perforators are absent or relatively tiny. To establish a safe technique for free fasciocutaneous flap elevation from the posterior calf region, we examined the number and location of the musculocutaneous perforators and the size of superficial cutaneous vessels at their origin from the popliteal artery in six formalinized cadavers. We found that all legs had at least one perforator either from the medial sural artery or the lateral sural artery. By contrast, we failed to find superficial cutaneous vessels of suitable size for microanastomosis in three legs, and there was no significant inverse relationship between the diameter of the superficial cutaneous artery and the number of musculocutaneous perforators. Our results suggest that the medial sural perforator flap and the lateral sural perforator flap might be the surgeon's first and second choice, respectively. The traditional posterior calf fasciocutaneous flap should be the third choice because our study suggests that its availability is doubtful. Another site is recommended, when preoperative Doppler study suggests that the existence of musculocutaneous perforator is in doubt. Two clinical cases, with a medial sural perforator flap and a lateral sural perforator flap, respectively, are presented.

Skin cancer screening on a fishing island and in an inland agricultural area of Japan.

We performed skin cancer screening from 2000 to 2004 at two locations in Japan's Oita Prefecture: Himeshima, a small fishing island, and Naoiri, an inland agricultural area. We found 108 and 21 cases of AK in Himeshima and Naoiri, respectively. None of the AKs transformed into SCC, and 21.7% of the AKs underwent spontaneous remission during our observation period. The prevalence and incidence of AK in Himeshima were five times higher than in Naoiri: 1,399 and 826 per 100,000 population, respectively, in the fishing village, vs. 261 and 164 in the agricultural community. Seven and three cases of BCC were observed in Himeshima and Naoiri, respectively. There were two cases of SCC in Himeshima. The highest risk ratio of skin types I to III was 9.2 in Himeshima. Although people engaged in outdoor occupations are thought to be more prone to skin cancer and precancerous skin lesions, our results suggested different potentials for AK in people engaged in different outdoor occupations.