Abstract
Metabolites of neural cells, is known to have a significant effect on the normal physiology and function of neurons in brain. However, whether they play a role in pathogenesis of neurodegenerative diseases is unknown. Here, we show that metabolites of neurons play essential role in the pathogenesis of Alzheimer's disease (AD). Firstly, in vivo and in vitro metabolites of cerebellar neurons both significantly induced the expression of Aβ-degrading enzymes in the hippocampus and cerebral cortex and promoted Aβ clearance. Moreover, metabolites of cerebellar neurons significantly reduced brain Aβ levels and reversed cognitive impairments and other AD-like phenotypes of APP/PS1 transgenic mice, in both early and late stages of AD pathology. On the other hand, metabolites of hippocampal neurons reduced the expression of Aβ-degrading enzymes in the cerebellum and caused cerebellar neurodegeneration in APP/PS1 transgenic mice. Thus, we report, for the first time, that metabolites of neurons not only are required for maintaining the normal physiology of neurons but also play essential role in the pathogenesis of AD and may be responsible for the regional-specificity of Aβ deposition and AD pathology.
Highlights
The fluid environment of neurons, which contains metabolites of neural cells, is known to have a significant effect on the normal physiology and function of neurons in brain [1]
We first found that expression of Ab degrading enzymes, neprilysin (NEP) and insulin degrading enzyme (IDE) in hippocampal neurons was induced by exposure to conditioned medium from cerebellar neurons (C-CM), which contains metabolites of cerebellar neurons, compared to treatment with conditioned medium from hippocampal neurons (H-CM) containing hippocampal neuron metabolites (Figure 1A and B)
Clearance of exogenous Ab by primary hippocampal neurons was significantly facilitated by the addition of C-CM, compared to treatment with H-CM via Ab degradation by IDE and NEP (Figure 1D and E)
Summary
The fluid environment of neurons, which contains metabolites of neural cells, is known to have a significant effect on the normal physiology and function of neurons in brain [1]. Little is known about the role of metabolites of neurons in the pathogenesis of neurodegenerative diseases. AD pathology is characterized by amyloid deposits in certain regions of the brain, such as the entorhinal cortex, hippocampus and basal forebrain. All of these areas are small, specialized structures in the brain that play critical roles in memory [6,7]. It has been reported that cerebellar neurons are more resistant to soluble oligomeric Ab an Ab species with potent neurotoxic activities [13], than the cortex and hippocampus, which are vulnerable to AD [14]. Little is known about the physiological mechanism underlying the regional specificity of Ab accumulation
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