Changes In Neural Development And Alzheimer's Disease, Tau, Synaptophysin And Hhrd1 Role

Alzheimer's disease is a most common neurodegenerative disease overhung the elderly population. Neurofibrillary tangles (NFT), which is consisted of hyperphosphorylated tau, and the synapse loss, are two pathological features in AD. There are a mass of misfolded proteins in the neurons in AD brain, including tau. The aggregation of aberrantly folded proteins brings about endoplasmic reticulum (ER) stress in neurons, which is partly responsible for the cell death in AD brain, and plays an essential role in the Alzheimer process. It is well documented that tau is hyperphosphorylated in human fetal brain, but no NFT formations can be detected, implied that the Alzheimer-like phosphorylation of tau protein may be not an eternal deleterious factor for neurons. Hippocampus is one of the most vulnerable regions in AD brain. The expression of Alzheimer-like tau protein and synapsin in human fetal brain at diverse gestational age and in AD hippocampus were investigated in the present study, the results showed that the expression of tau and synapsin I in fetal hippocampus was different from AD. hHrd1, a newly identified ER resident E3 ligase, was extensively colocalized with hyperphosphorylated tau in the hippocampal neurons in AD, and their expression showed an inverted change, indicated that the hHrdl mediated ER associated protein degradation (ERAD) process might be involved in tau degradation.1. Alzheimer-like phosphorylated fetal tau (F-tau) was widely expressed in fetal hippocampus at different gestational ages. The Alzheimer-like F-tau (AT8 epitope) was mainly existed in the nucleus during fetal brain development, however, normal F-tau (taul epitope) was primarily expressed in the cytosol. Taul positive hippocampal neurons can be detected both in AD patients and in the control, however, their subcelluar distribution was different, the cytosol and the nucleus can both be labeled in the control hippocampal neurons, whereas in AD hippocampus taul positive cells were mostly NFT-like formations, the nucleus can not be labeled. Besides a considerable of NFT formations, there are some AT8 positive nucleus in the CA3 subfield and dentate gyrus in AD hippocampus, and the nuclear state was similar to fetal stage, implied that the cell cycle was reactivated in these neurons. AT8 was highly expressed in the nucleus in the cultured rat hippocampal primary neurons in day1, and then was mainly distutributed in cytosol and axons. Taul can not be detected in the nucleus throughout the whole culture process. The immunoblot result showed that the molecular weight of Alzheimer-like F-tau in human fetal hippocampus was different from rat fetal brain, whereas was crossover with AD and control hippocampus. We proposed that the Alzheimer-like F-tau plays a role in cell mitosis and earlier differentiation in the central nervous system, and the appearance of AT8 positive nucleus in AD hippocampus may be an early neuroprotective response to cell impairment.2. hHrd1 is an newly identified ER resident E3 ligase, previous in vitro studies showed that it can mediate several kinds of protein degradation through ERAD pathway. Up until now, the expression and function of hHrd1 in human brain still remains elusive. By using double-labeling immunocytochemistry and morphometry in the present study, we found that hHrd1 was extensively expressed in neurons and astrocytes in human hippocampus. hHrd1 expression was up-regulated in the hippocampal CA1 subfield in AD compared with the age-matched control, which implied that hHrd1 might be associated with the progress of Alzheimer process. hHrd1 was colocalized with hyperphosphorylated tau in the hippocampal neurons in AD, and their expression showed a converse change, implied that hHrd1 mediated ERAD might be involved in tau degradation.3. Synapsin I is a most abundant synaptic vesicle protein, and is principally distributed in nerve terminals in mature neurons, however, the expression and distribution of synapsin I in developing human fetal brain is still unclear. Herein, we found that synapsin I was widely expressed in human fetal brain at gestational week (gw) 9, it can be detected in the hippocampus from gw10, and the expression level showed an uptrend accompanied with the growth of gestational age. synapsin I immunitivity can be detected in the cell body in the earlier fetal development (gw9-17), some positive fibers can also be labeled at these stages, which was very different form later fetal stages and the adult brain. The characters of synapsin I expression and distribution in the hippocampus at later gestational stage were similar with the aged control and AD patient, whereas the expression level was comparatively low. Our results showed that alterations of synapsin I expression and distribution in fetal hippocampus were associated with the development of hippocampal formation, implied that the function of synapsin I during the earlier neuronal development was more than the regulation of neurotransmitter release, it may also be involved in the modulation of neuronal development and differentiation.In conclusion, we proposed that the Alzheimer-like phosphorylation of tau protein at fetal stage may play a role in neuronal mitosis and differentiation, tau hyperphosphorylation and re-distribution in the nucleus in AD hippocampus should be an earlier neuronal self-protective effect, and the aggregation of hyperphosphorylated tau may be associated with the unbalance of its dynamic phosphorylation and the abnormal degradation. hHrd1 may have neuroprotective effect in AD hippocampus, while the subcelluar re-distribution of tau in the elderly and AD patient made it possible for hHrd1 mediated tau degradation. The expression and distribution of synapsin I in the earlier developing fetal brain implied that it may played a more role than modulating neurotransmitter release, it might be associated with the developing and remodeling of hippocampal formation.