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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. We find that truncating mutation results in SORL1 haploinsufficiency and enlarged endosomes in human neurons. Analysis of isogenic SORL1 wildtype, heterozygous, and homozygous null neurons demonstrates that, whereas SORL1 haploinsufficiency results in endosome dysfunction, complete loss of SORL1 leads to additional defects in lysosome function and autophagy. Neuronal endolysosomal dysfunction caused by loss of SORL1 is relieved by extracellular antisense oligonucleotide-mediated reduction of APP protein, demonstrating that PSEN1, APP, and SORL1 act in a common pathway regulating the endolysosome system, which becomes dysfunctional in AD.

Cell and molecular biology analyses of sporadic Alzheimer's disease brain are confounded by clinical variability, ageing and genetic heterogeneity. Therefore, we used single-nucleus RNA sequencing to characterize cell composition and gene expression in the cerebral cortex in early-onset, monogenic Alzheimer's disease. Constructing a cellular atlas of frontal cortex from 8 monogenic AD individuals and 8 matched controls, provided insights into which neurons degenerate in AD and responses of different cell types to AD at the cellular and systems level. Such responses are a combination of positively adaptive and deleterious changes, including large-scale changes in synaptic transmission and marked metabolic reprogramming in neurons. The nature and scale of the transcriptional changes in AD emphasizes the global impact of the disease across all brain cell types.

In addition to increased aberrant protein aggregation, inflammation has been proposed as a key element in the pathogenesis and progression of Alzheimer’s disease. How inflammation interacts with other disease pathways and how protein aggregation increases during disease are not clear. We used single molecule imaging approaches and membrane permeabilisation assays to determine the effect of chronic exposure to TNF, a master proinflammatory cytokine, on protein aggregation in human induced pluripotent stem cell-derived neurons harbouring monogenic Alzheimer’s disease mutations. We report that exposure of Alzheimer’s disease, but not control, neurons to TNF induces substantial production of extracellular protein aggregates. Aggregates from Alzheimer’s disease neurons are composed of amyloid-β and α-synuclein and induce significant permeabilisation of lipid membranes in an assay of pathogenicity. These findings provide support for a causal relationship between two crucial processes in Alzheimer’s disease pathogenesis, and suggest that targeting inflammation, particularly TNF, may have beneficial downstream effects on ameliorating aberrant protein aggregation and accumulation.

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