Mouse anti-Human VPS35 monoclonal antibody, clone 3E4

Since the late 1980's, protein phosphorylation-mediated mechanisms have been recognized as regulators of sorting and processing of the Alzheimer's amyloid precursor (APP). These phospho-state-sensitive steps, in turn, determine the quality and quantity of A beta generation. Here, we review several recent advances in this field, including new evidence that: (1) the phospho-state of APP threonine-668 does not obviously regulate APP sorting, A beta generation or A beta speciation; (2) P-secretase (BACE) recycling is regulated by the phospho-state of the BACE cytoplasmic tail, but without impact on A beta generation or speciation; (3) contrary to its well-documented acute actions, chronic protein kinase C activation increases A beta generation, and (4) sorting of APP and/or its alpha- and beta-carboxyl-terminal fragments (C83 and C99, respectively) toward the trans-Golgi network is under the influence of presenilins and the VPS35/retromer. With the recent discovery of genetic linkage between the risk for Alzheimer's disease (AD) and polymorphisms in SORL1, a gene belonging to the sortilin class of trafficking proteins, the membrane protein cell biology of APP has emerged as a central focus For investigators seeking to understand the basis of common forms of AD and thereby uncover new therapeutic opportunities for its treatment and/or prevention.

Objective: To identify new genes and risk factors associated with frontotemporal dementia (FTD). Several genes and loci have been associated with different forms of FTD, but a large number of families with dementia do not harbor mutations in these genes. Design: Whole-exome sequencing and whole-genome genotyping were performed in all patients. Genetic variants obtained from whole-exome sequencing were integrated with the data obtained from whole-genome genotyping. Setting: Database of the Behavioral Neurology Outpatient-Clinic of the Department of Neurology, Istanbul Faculty of Medicine, Istanbul, Turkey. Patients: Forty-four Turkish patients with an FTD-like clinical diagnosis were included in the study. Relatives were screened when appropriate. Main Outcome Measure: Mutations in the triggering receptor expressed on myeloid cells 2 gene (TREM2). Results: In 3 probands with FTD-like disease, we identified different homozygous mutations in TREM2 that had previously been associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). None of these 3 patients had a typical clinical presentation of PLOSL: they presented with behavioral change and subsequent cognitive impairment and motor features but without any bone cysts or bone-associated phenotypes. Imaging showed white matter abnormalities as well as frontal atrophy in all 3 patients. Conclusions: Our results show that TREM2 is responsible for an unexpectedly high number of dementia cases in our cohort, suggesting that this gene should be taken into account when mutations in other dementia genes are excluded. Even for complex syndromes such as dementia, exome sequencing has proven to be a rapid and cost-effective tool to identify genetic mutations, allowing for the association of clinical phenotypes with unexpected molecular underpinnings. JAMA Neurol. 2013;70(1):78-84. Published online October 8, 2012. doi:10.1001/jamaneurol.2013.579