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SorLA deficiency dissects amyloid pathology from tau and cholinergic neurodegeneration in a mouse model of Alzheimer's disease.
- Source :
-
Journal of Alzheimer's disease : JAD [J Alzheimers Dis] 2013; Vol. 33 (2), pp. 357-71. - Publication Year :
- 2013
-
Abstract
- Sortilin-related receptor with A-type repeats (SorLA, also known as LR11) has been implicated in Alzheimer's disease (AD). Thus, genetic studies associated SorLA gene variants with the risk of sporadic AD. Also, in vitro and in vivo studies showed that SorLA impairs processing of the amyloid-β protein precursor (AβPP) to amyloid-β. In particular, it has been found that loss of SorLA accelerates senile plaque deposition in mouse models overexpressing mutant forms of human AβPP and presenilin 1. Here we tested the possibility that SorLA deficiency also interferes with behavioral and neuropathological endpoints in an alternative murine AD model, the AD10 anti-nerve growth factor (NGF) mouse, in which amyloid-β accumulation derives from the altered processing of endogenous AβPP. In addition to alterations in AβPP processing, AD10 mice also show cholinergic deficit and tau hyperphosphorylation resulting in behavioral deficits in learning and memory paradigms. We found that the loss of SorLA not only exacerbates early amyloid pathology but, at the same time, protects from cholinergic deficit and from early phospho-tau mislocalization. The results show that in the AD10 anti-NGF mouse model the AβPP processing-related aspects of neurodegeneration can be dissociated from those related to tau posttranslational processing and to cholinergic phenotypic maintenance by modulation of SorLA expression. We suggest that SorLA regulates different aspects of neurodegeneration in a complex way, supporting the hypothesis that SorLA expression might be critical not only for amyloid-related pathology but also for other cellular processes altered in AD.
- Subjects :
- Alzheimer Disease pathology
Amyloid metabolism
Amyloidosis metabolism
Amyloidosis pathology
Animals
Cerebral Cortex pathology
Cerebral Cortex physiology
Cholinergic Neurons pathology
Disease Models, Animal
Female
Male
Maze Learning physiology
Membrane Transport Proteins deficiency
Membrane Transport Proteins metabolism
Memory Disorders genetics
Memory Disorders metabolism
Memory Disorders pathology
Mice
Mice, 129 Strain
Mice, Knockout
Nerve Degeneration genetics
Nerve Degeneration metabolism
Nerve Degeneration pathology
Phosphorylation physiology
Receptor, trkA metabolism
Receptors, LDL deficiency
Receptors, LDL metabolism
Alzheimer Disease genetics
Alzheimer Disease metabolism
Amyloidosis genetics
Cholinergic Neurons metabolism
Membrane Transport Proteins genetics
Receptors, LDL genetics
tau Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1875-8908
- Volume :
- 33
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of Alzheimer's disease : JAD
- Publication Type :
- Academic Journal
- Accession number :
- 22986780
- Full Text :
- https://doi.org/10.3233/JAD-2012-121399