Axonal And Dendritic Changes Are Associated With The Development Of Diabetic Encephalopathy

Diabetic encephalopathy is the complication of diabetes in central nervious system,which has the characteristics of neuropathological and electrophysiological changessuch as modest cerebral atrophy,(periventricular) white matter lesions (WML) anddelayed latencies of evoked potentials. However, its underlying mechanism is not clear.Resent studies show that axonopathy is closely linked to and promotes a subset ofneurological diseases including Alzheimer’s disease (AD), which is considered as “type3diabetes”. The present of axonopathy is earlier than the two classic pathologicalchanges of AD—senile plaque (SP) and neurofibrillary tangle (NFT), and axonopathy isconsidered as an important role in the underlying mechanism of pathologenesis in AD,but its involvement in the development of diabetic encephalopathy remains unknown.Here, we aimed to ascertain the role of axonopathy in the development of diabeticencephalopathy and the relationship between diabetic encephalopathy and AD. Astreptozotocin (STZ)-induced diabetic rat model was used. The Y-maze and alternativeelectric stimulus Y-maze, in vivo neuronal tracing, immunohistochemistry and westernblot analysis were performed to evaluate the cognitive functions, axonal and dendriticchanges and the expressions of β-amyloid (Aβ) and hyperphosphorylated tau in relationto the development of diabetic encephalopathy in this diabetic model. Diabetic ratspresented polydipsia, polyphagia, hyperdiuresis, reduced body weight and elevated fasting blood glucose. Compared to the controls, diabetic rats showed the significantlydecreased locomotor activity and the percentage of spontaneous alternation in theY-maze test, which indicated a notable impairment of spatial learning and memory inthe diabetic rats. In the alternative electric stimulus Y-maze task, it was found that theTRT was significantly elevated in the diabetic rats (65.8±3.5s) compared to the controls(40.4±4.3s), and the RAAR in the diabetic rats was threefold higher than that in thenon-diabetic rats, although there were no obvious differences of the ET between the twogroups. These data suggested that the diabetic animals exhibited a cognitive dysfunctionwith a slow response in the memory processing. Axonal and dendritic changes, termedaxonopathy and dendropathy, respectively, that mainly manifested as typical swollenaxons and varicosities and dendrites, were observed in the hippocampus and the sensoryand entorhinal cortexes in the diabetic rats, whereas such changes were scarce in thecontrols. In addition, axonal leakage was occasionally observed in the diabetic rats. Thecorrelation analysis showed that the positive correlation was found in fasting bloodglucose and axonal and dendritic changes, and it was also in cognitive function andaxonal and dendritic changes. The site-specific hyperphosphorylated tau, but notdeposits of Aβ, was detected in the diabetic rat brains. Compared to the non-diabeticgroup, the expression of P-tau in the hippocampus and the cortex were significantlyincreased in the diabetic group, however, an increased expression of Tau-5was found inthe hippocampus in the diabetic group, but not in the cortex. These data reveal a keyrole of axonopathy and dendropathy (neuritic changes) in the course of diabeticencephalopathy that is accompanied with the site-specific hyperphosphorylated taurather than Aβ accumulation, which may be a mechanism contributing to the cognitive impairment in diabetic encephalopathy and an early link to the neuropathologicalprocesses of AD.