Constitutive activation of WASp leads to abnormal cytotoxic cells with increased granzyme B and degranulation response to target cells.

X-linked neutropenia (XLN) is caused by gain-of-function mutations in the actin regulator Wiskott-Aldrich Syndrome protein (WASp). XLN patients have reduced numbers of cytotoxic cells in peripheral blood; however, their capacity to kill tumor cells remains to be determined. Here, we examined NK and T cells from 2 patients with XLN harboring the activating WASpL270P mutation.

The Proteome of the Dentate Terminal Zone of the Perforant Path Indicates Presynaptic Impairment in Alzheimer Disease.

Synaptic dysfunction is an early pathogenic event in Alzheimer disease (AD) that contributes to network disturbances and cognitive decline. Some synapses are more vulnerable than others, including the synapses of the perforant path, which provides the main excitatory input to the hippocampus. To elucidate the molecular mechanisms underlying the dysfunction of these synapses, we performed an explorative proteomic study of the dentate terminal zone of the perforant path.

Overexpression of SNX3 Decreases Amyloid-β Peptide Production by Reducing Internalization of Amyloid Precursor Protein.

Background: Sorting nexins (SNXs) have diverse functions in protein sorting and membrane trafficking. Recently, single-nucleotide polymorphisms in SNX3 were found to be associated with Alzheimer disease. However, it remains unknown whether SNX3 participates in amyloid (A)β peptide production.

Exercise and BDNF reduce Aβ production by enhancing α-secretase processing of APP.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by aggregation of toxic forms of amyloid β peptide (Aβ). Treatment strategies have largely been focused on inhibiting the enzymes (β- and γ-secretases) that liberate Aβ from the amyloid precursor protein (APP). While evidence suggests that individuals who exercise regularly are at reduced risk for AD and studies of animal models demonstrate that running can ameliorate brain Aβ pathology and associated cognitive deficits, the underlying mechanisms are unknown.

Extracellular Vesicle-Associated Aβ Mediates Trans-Neuronal Bioenergetic and Ca-Handling Deficits in Alzheimer's Disease Models.

Alzheimer's Disease (AD) is an age-related neurodegenerative disorder in which aggregation-prone neurotoxic amyloid β-peptide (Aβ) accumulates in the brain. Extracellular vesicles (EVs) are small 50-150 nanometer membrane vesicles that have recently been implicated in the prion-like spread of self-aggregating proteins. Here we report that EVs isolated from AD patient CSF and plasma, from the plasma of two AD mouse models, and from the medium of neural cells expressing familial AD presenilin 1 mutations, destabilize neuronal Ca homeostasis, impair mitochondrial function, and sensitize neurons to excitotoxicity.

Endogenous APP accumulates in synapses after BACE1 inhibition.

BACE1-mediated cleavage of APP is a pivotal step in the production of the Alzheimer related Aβ peptide and inhibitors of BACE1 are currently in clinical development for the treatment of Alzheimer disease (AD). While processing and trafficking of APP has been extensively studied in non-neuronal cells, the fate of APP at neuronal synapses and in response to reduced BACE1 activity has not been fully elucidated. Here we examined the consequence of reduced BACE1 activity on endogenous synaptic APP by monitoring N- and C-terminal APP epitopes by immunocytochemistry.