Abstract
We investigated early phenotypes caused by familial Alzheimer's disease (fAD) mutations in isogenic human iPSC-derived neurons. Analysis of neurons carrying fAD PS1 or APP mutations introduced using genome editing technology at the endogenous loci revealed that fAD mutant neurons had previously unreported defects in the recycling state of endocytosis and soma-to-axon transcytosis of APP and lipoproteins. The endocytosis reduction could be rescued through treatment with a β-secretase inhibitor. Our data suggest that accumulation of β-CTFs of APP, but not Aβ, slow vesicle formation from an endocytic recycling compartment marked by the transcytotic GTPase Rab11. We confirm previous results that endocytosis is affected in AD and extend these to uncover a neuron-specific defect. Decreased lipoprotein endocytosis and transcytosis to the axon suggest that a neuron-specific impairment in endocytic axonal delivery of lipoproteins and other key materials might compromise synaptic maintenance in fAD.
Highlights
Alzheimer’s disease (AD) is a progressive and devastating neurodegenerative disorder that affects more than 30 million people worldwide, including 11% of those over 65 years of age and 32% of those over 85 (Alzheimer’s Association, 2014)
Our study reveals that a common early defect among familial AD (fAD) PS1 and amyloid precursor protein (APP) mutations is APP b C-terminal fragments (b-CTFs) accumulation-induced impairment of a key neuron-specific traffic pathway, soma-to-axon transcytosis, caused by defects in the recycling endosome
We found that PS1WT/DE9 and PS1DE9/DE9 neurons exhibited a modest but significant increase in intracellular APP staining in the cell body (Figure 1A)
Summary
Alzheimer’s disease (AD) is a progressive and devastating neurodegenerative disorder that affects more than 30 million people worldwide, including 11% of those over 65 years of age and 32% of those over 85 (Alzheimer’s Association, 2014). AD is characterized by progressive cerebral dysfunction, memory loss, synapse loss, and neuronal impairment leading to cell death. There are no disease-modifying treatments that can cure or reduce the progression of AD. AD is segmented into two populations: sporadic AD (sAD), where the underlying primary cause is not known, and rare autosomaldominant mutations causing familial AD (fAD) (Gatz et al., 2006). Many experimental findings regarding AD have come from overexpression studies or studies of non-neuronal cells that lack the unique polarization and compartmentalization of neurons
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