| Extensive loss of hippocampal neurons serves a pathological basis for irreversible cognitive impairment in patients with Alzheimer's disease(AD).However,this characteristic cannot be replicated by transgenic mouse models,and its underlying mechanisms are unclear.Here,we present evidence that different expression patterns of amyloid-protein precursor(APP)secretases in human and mouse hippocampal neurons are a decisive cause of species difference in the susceptibility to A?pathogenesis.Cell bodies of both pyramidal and granular neurons did not appear to undergo A? deposits in the 10-month-old transgenic mutant human APP/presenilin-1(PS1)mice.They expressed high levels of non-amyloidogenic ?-secretase,and its neuroprotective products soluble APP?,but low levels of amyloidogenic ?-secretase and y-secretase,and a neurotoxic product,A?42 peptide.Unlike those found in the mouse,human hippocampal neuronal cell bodies expressed ?-secretase and y-secretase,but not ?-secretase,which could increase A? generation,thus undergoing death in response to various pathological conditions.Increased hippocampal neuronal apoptosis at 48 h following local micro injection of ?-secretase antibody AD AM10 into the hippocampus of APP/PS1 mice further suggests that high ?-secretase expression in mouse neuronal cell bodies is a factor in the paucity of neuronal loss in AD-like pathology.Therefore,selective down regulation of brain ?-secretase in transgenic AD models will better replicate the disease spectrum,including decreased brain soluble A?PP levels and massive neuronal loss in AD patients,and be beneficial for preclinical therapeutic evaluation of AD.Alzheimer's disease(AD)is a common neurodegenerative disease in the elderly,characterized by progressive cognitive dysfunction.Although the etiology of AD is not clear,a large number of studies have shown that the brain ?-amyloid(A?)cascade plays a central role in the occurrence and development of AD.Therefore,it is of great significance to promote the clearance of A? in the brain and prevent its aggregation.Recent studies suggest that the glymphatic system is the main pathway for the clearance of macromolecular metabolites including A? from the brain,but the role of glymphatic system dysfunction in the pathogenesis of AD needs to be further clarified.To address this issue,we investigated the effect of knockout of the aquaporin 4(AQP4)gene,a key regulatory molecule for the clearance of glial lymph nodes,on the early AD-like pathology of APP/PS1 mice.The results showed that there was no significant A? accumulation in hippocampus and cerebral cortex of APP/PS1 mice at 3 months of age.The expression levels of A? transport and clearance makers including neprilysin,insulin degrading enzyme and low density lipoprotein receptor related protein 1,as well as synaptophysin and cognitive function were not significantly abnormal,but there were significant decreases in glial lymphatic transport capacity,activation of microglia and astrocytes in hippocampus and cortex accompanied by increased uptake of A? and increased expression of interleukin-1? in the hippocampus and interleukin-6 in the cortex and mild spatial learning decline.The aqp4 gene knockout further aggravated the damage of glial lymphatic clearance,slightly increased microglia activation and inflammatory response,but reduced the activation of reactive astrocytes,and did not further aggravate the A? load and synaptic and memory impairment in the brain.The results suggested that the glymphatic clearance malfunction exists in the early stage of AD,and due to the relatively normal function of A? enzymatic transport system,AQP4 deficiency does not lead to A? deposition,but increases the load of phagocytosis and clearance of A?by microglia,leading to activation and inflammatory response.Therefore,it is beneficial to delay the onset of AD by targeting AQP4 to improve the function of glymphatic clearance. |
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