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New research by Ju-Hyun Lee, Ralph Nixon, and members of the Nixon lab has been posted on Research Square, the online platform where researchers share their research findings as preprints and is currently under review at Nature Neuroscience. The piece titled, “Autophagy-lysosomal dysfunction, intraneuronal amyloidosis, and selective neuron death yield senile plaques in preclinical late-onset Alzheimer’s Disease,” concludes that findings in human sporadic Alzheimer’s Disease (AD) brains corroborate and affirm the extensive analyses in mouse models that have highlighted the exceptionally early development of autophagy-lysosomal pathway (ALP) dysfunction stemming in major part from faulty lysosomal acidification. Consistent with the observations in AD mouse models, the researchers document in human AD, an essentially identical phenotype of ALP dysfunction associated with PANTHOS and with intraneuronal β-amyloidogenesis and neuron death, yielding extracellular plaque formation. This mechanism, defined by impaired autophagy and lysosomal dysfunction, likely precedes the classical extracellular amyloid seeding, providing new insights into the early intraneuronal origins of AD.