The Inside-Out Amyloid Hypothesis and Synapse Pathology in Alzheimer's Disease.
Författare
Summary, in English
Cumulative evidence in brains and cultured neurons of Alzheimer's disease (AD) transgenic mouse models, as well as in human postmortem AD brains, highlights that age-related increases in β-amyloid peptide (Aβ), particularly in endosomes near synapses, are involved in early synapse dysfunction. Our immunoelectron microscopy and high-resolution immunofluorescence microscopy studies show that this early subcellular Aβ accumulation leads to progressive Aβ aggregation and pathology, particularly within dystrophic neurites and synapses. These studies confirm that neuritic/synaptic Aβ accumulation is the nidus of plaque formation. Aβ-dependent synapse pathology in AD models is modulated by synaptic activity and is plaque independent. The amyloid precursor protein (APP) is normally transported down neurites and appears to be preferentially processed to Aβ at synapses. Synapses are sites of early Aβ accumulation and aberrant tau phosphorylation in AD, which alter the synaptic composition at early stages of the disease. Elucidating the normal role of APP, and potentially of Aβ, at synapses should provide important insights into the mechanism(s) of Aβ-induced synapse dysfunction in AD and how to therapeutically mitigate these dysfunctions. © 2013 S. Karger AG, Basel.
Avdelning/ar
Publiceringsår
2014
Språk
Engelska
Sidor
142-146
Publikation/Tidskrift/Serie
Neurodegenerative Diseases
Volym
13
Issue
2-3
Länkar
Dokumenttyp
Artikel i tidskrift
Förlag
Karger
Ämne
- Neurology
Status
Published
Forskningsgrupp
- Experimental Dementia Research
ISBN/ISSN/Övrigt
- ISSN: 1660-2862