Lysosomal NEU1 deficiency affects amyloid precursor protein levels and amyloid-β secretion via deregulated lysosomal exocytosis.
Alzheimer's disease (AD) belongs to a category of adult neurodegenerative conditions, which are associated with intracellular and extracellular accumulation of neurotoxic protein aggregates. Understanding how these aggregates are formed, secreted and propagated by neurons has been the subject of intensive research, but so far no preventive or curative therapy for AD is available, and clinical trials have been largely unsuccessful. Here we show that deficiency of the lysosomal sialidase NEU1 leads to the spontaneous occurrence of an AD-like amyloidogenic process in mice. This involves two consecutive events linked to NEU1 loss-of-function--accumulation and amyloidogenic processing of an oversialylated amyloid precursor protein in lysosomes, and extracellular release of Aβ peptides by excessive lysosomal exocytosis. Furthermore, cerebral injection of NEU1 in an established AD mouse model substantially reduces β-amyloid plaques. Our findings identify an additional pathway for the secretion of Aβ and define NEU1 as a potential therapeutic molecule for AD.
Department of Genetics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Ida
I
Annunziata
Annette
A
Patterson
Danielle
D
Helton
Huimin
H
Hu
Simon
S
Moshiach
Elida
E
Gomero
Ralph
R
Nixon
Alessandra
A
d'Azzo
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000196:embryology; D000001:Calcimycin / Q000378:metabolism; D002460:Cell Line; D000229:Dependovirus / Q000378:metabolism; D005089:Exocytosis / Q000502:physiology*; D006624:Hippocampus / Q000196:embryology / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009081:Mucolipidoses / Q000235:genetics*; D009439:Neuraminidase / Q000235:genetics* / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D012307:Risk Factors
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000001:Calcimycin; C110128:Neu1 protein, mouse; D009439:Neuraminidase