Clearance of beta-amyloid and tau aggregates is size dependent and altered by an inflammatory challenge.

Extracellular beta-amyloid aggregation and inflammation are in a complex and not fully understood interplay during hyperphosphorylated tau aggregation and pathogenesis of Alzheimer's disease. Our group has previously shown that an immune challenge with tumour necrosis factor alpha can alter extracellular beta-sheet containing aggregates in human-induced pluripotent stem cell-derived cortical neurons carrying familial Alzheimer's disease-related presenilin 1 mutations. Here, using single-molecule detection and super-resolution imaging techniques, we quantified and characterized the intra- and extracellular beta-amyloid and AT8-positive tau aggregates.

APP antisense oligonucleotides reduce amyloid-β aggregation and rescue endolysosomal dysfunction in Alzheimer's disease.

APP gene dosage is strongly associated with Alzheimer's disease (AD) pathogenesis. Genomic duplication of the APP locus leads to autosomal dominant early-onset AD. Individuals with Down syndrome (trisomy of chromosome 21) harbour three copies of the APP gene and invariably develop progressive AD with highly characteristic neuropathological features.

4R tau drives endolysosomal and autophagy dysfunction in frontotemporal dementia.

Dysfunction of the neuronal endolysosome and macroautophagy/autophagy pathway is emerging as an important pathogenic mechanism in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The (valosin-containing protein) gene is of significant relevance, directly implicated in both FTD and ALS. In our recent study, we used patient-derived stem cells to study the effects of mutations on the endolysosome and autophagy system in human cortical excitatory neurons.

Elevated 4R tau contributes to endolysosomal dysfunction and neurodegeneration in VCP-related frontotemporal dementia.

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two incurable neurodegenerative diseases that exist on a clinical, genetic and pathological spectrum. The VCP gene is highly relevant, being directly implicated in both FTD and ALS. Here, we investigate the effects of VCP mutations on the cellular homoeostasis of human induced pluripotent stem cell-derived cortical neurons, focusing on endolysosomal biology and tau pathology.

Endolysosome and autophagy dysfunction in Alzheimer disease.

Abnormalities of the neuronal endolysosome and macroautophagy/autophagy system are an early and prominent feature of Alzheimer disease (AD). is notable as a gene in which mutations are causal for a rare, autosomal dominant form of AD, and also variants that increase the risk of developing the common form of late-onset AD. In our recent study, we used patient-derived stem cells and CRISPR engineering to study the effects of mutations on the endolysosome and autophagy system in human forebrain neurons.

SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy network.

Dysfunction of the endolysosomal-autophagy network is emerging as an important pathogenic process in Alzheimer's disease. Mutations in the sorting receptor-encoding gene SORL1 cause autosomal-dominant Alzheimer's disease, and SORL1 variants increase risk for late-onset AD. To understand the contribution of SORL1 mutations to AD pathogenesis, we analyze the effects of a SORL1 truncating mutation on SORL1 protein levels and endolysosome function in human neurons.

Altered γ-Secretase Processing of APP Disrupts Lysosome and Autophagosome Function in Monogenic Alzheimer's Disease.

Abnormalities of the endolysosomal and autophagy systems are found in Alzheimer's disease, but it is not clear whether defects in these systems are a cause or consequence of degenerative processes in the disease. In human neuronal models of monogenic Alzheimer's disease, APP and PSEN1 mutations disrupt lysosome function and autophagy, leading to impaired lysosomal proteolysis and defective autophagosome clearance. Processing of APP by γ-secretase is central to the pathogenic changes in the lysosome-autophagy system caused by PSEN1 and APP mutations: reducing production of C-terminal APP by inhibition of BACE1 rescued these phenotypes in both APP and PSEN1 mutant neurons, whereas inhibition of γ-secretase induced lysosomal and autophagic pathology in healthy neurons.

KIF1A mediates axonal transport of BACE1 and identification of independently moving cargoes in living SCG neurons.

Neurons rely heavily on axonal transport to deliver materials from the sites of synthesis to the axon terminals over distances that can be many centimetres long. KIF1A is the neuron-specific kinesin with the fastest reported anterograde motor activity. Previous studies have shown that KIF1A transports a subset of synaptic proteins, neurofilaments and dense-core vesicles.