Abstract
There is now compelling evidence that the neurodegenerative process in Alzheimer’s disease (AD) begins in synapses. Loss of synaptic proteins and functional synapses in the amyloid precursor protein (APP) transgenic mouse models of AD is well established. However, what is the earliest age at which such loss of synapses occurs, and whether known markers of AD progression accelerate functional deficits is completely unknown. We previously showed that RanBP9 overexpression leads to robustly increased amyloid β peptide (Aβ) generation leading to enhanced amyloid plaque burden in a mouse model of AD. In this study we compared synaptic protein levels among four genotypes of mice, i.e., RanBP9 single transgenic (Ran), APΔE9 double transgenic (Dbl), APΔE9/RanBP9 triple transgenic (Tpl) and wild-type (WT) controls. We found significant reductions in the levels of synaptic proteins in both cortex and hippocampus of 5- and 6-months-old but not 3- or 4-months-old mice. Specifically, at 5-months of age, rab3A was reduced in the triple transgenic mice only in the cortex by 25% (p<0.05) and gap43 levels were reduced only in the hippocampus by 44% (p<0.01) compared to wild-type (WT) controls. Interestingly, RanBP9 overexpression in the Tpl mice reduced gap43 levels by a further 31% (p<0.05) compared to APΔE9 mice. RanBP9 also further decreased the levels of drebrin in the hippocampus by 32% (p<0.01) and chromogranin in the cortex by 24% (p<0.05) compared to APΔE9 mice. At 6-months of age, RanBP9 expression in the cortex led to further reduction of rab3A by 30% (p<0.05) and drebrin by 38% (p<0.01) compared to APΔE9 mice. RanBP9 also increased Aβ oligomers in the cortex at 6 months. Similarly, in the hippocampus, RanBP9 expression further reduced rab3A levels by 36% (p<0.01) and drebrin levels by 33% (p<0.01). Taken together these data suggest that RanBP9 overexpression accelerates loss of synaptic proteins in the mouse brain.
Highlights
Alzheimer’s disease (AD) is a devastating neurodegenerative disease of elderly that affects more than 35 million people worldwide [1]
We previously demonstrated that RanBP9 forms tripartite protein complex by binding with amyloid precursor protein (APP), BACE1 and low-density lipoprotein receptor-related protein (LRP), thereby increases amyloid b peptide (Ab) generation in both transformed cells and primary neurons by enhancing b-secretase-mediated processing of APP at the cost of a-secretase processing [22]
Loss of synapses and synaptic proteins is well established in AD brains as well as mouse models of AD, the earliest ages when such anomaly begins to appear and whether markers of AD progression have any influence on such a loss is unknown
Summary
Alzheimer’s disease (AD) is a devastating neurodegenerative disease of elderly that affects more than 35 million people worldwide [1]. Accumulating data suggest that the progression of AD is more tightly associated with synapse degeneration rather than amyloid plaques or neurofibrillary tangles. Substantial evidence indicates that in AD, there is a decrease in the number of synapses, which occurs later than Ab accumulation and correlates with disease progression [2,3,4]. Ultrastructural analysis of autopsied brain tissue from patients with AD within few years after clinical onset revealed progressive synapse loss in the hippocampus, the frontal and inferior parietal cortex and entorhinal cortex [6,7]. The role of synaptic proteins, especially their progressive loss in causing dementia has been the subject of increasing interest ever since the correlation between loss of synapses and AD was first established [8].
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