Abstract
BackgroundEarly cognitive impairment in Alzheimer Disease (AD) is thought to result from the dysfunctional effect of amyloid beta (Aβ) oligomers targeting the synapses. Some individuals, however, escape cognitive decline despite the presence of the neuropathologic features of AD (Aβ plaques and neurofibrillary tangles). We term this group Non-Demented with AD Neuropathology or NDAN. The present study illustrates one putative resistance mechanism involved in NDAN cases which may suggest targets for the effective treatment of AD.ResultsHere we describe the localization of Aβ oligomers at the postsynapse in hippocampi from AD cases. Notably, however, we also found that while present in soluble fractions, Aβ oligomers are absent from hippocampal postsynapses in NDAN cases. In addition, levels of phosphorylated (active) CREB, a transcription factor important for synaptic plasticity, are normal in NDAN individuals, suggesting that their synapses are functionally intact. Analysis of Zn2+ showed that levels were increased in both soluble fractions and synaptic vesicles in AD hippocampi, paralleled by a decrease of expression of the synaptic vesicle Zn2+ transporter, ZnT3. Conversely, in NDAN individuals, levels of Zn2+ in soluble fractions were significantly lower than in AD, whereas in synaptic vesicles the levels of Zn2+ were similar to AD, but accompanied by preserved expression of the ZnT3.ConclusionsTaken together, these data illustrate that despite substantial AD neuropathology, Aβ oligomers, and increased synaptic vesicle Zn2+, susceptible brain tissue in these aged NDAN individuals features, as compared to symptomatic AD subjects, significantly lower total Zn2+ levels and no association of Aβ oligomers with the postsynapse, which collectively may promote the maintenance of intact cognitive function.
Highlights
Cognitive impairment in Alzheimer Disease (AD) is thought to result from the dysfunctional effect of amyloid beta (Aβ) oligomers targeting the synapses
The recognized existence of Non-Demented with Alzheimer’s Neuropathology (NDAN) individuals suggests that there are mechanisms by which the aging human brain may cope with cognitive dysfunction brought about by Aβ and neurofibrillary tangles (NFT)’s; and determining the protective molecular mechanisms involved in these resistant individuals could lead to the identification of novel targets for the development of effective therapeutic approaches [9]
Groups were designated based on Braak and plaque stages according to CERAD specifications and the Mini Mental State Exam (MMSE) test scores as described in Diagnosis n Age Sex
Summary
Cognitive impairment in Alzheimer Disease (AD) is thought to result from the dysfunctional effect of amyloid beta (Aβ) oligomers targeting the synapses. The National Institute of Health/National Institute on Aging and the Alzheimer’s Association have recently included such individuals in their joint official guidelines for neuropathologic assessment of AD and classified them as individuals who have AD neuropathologic changes in the absence of cognitive impairment [9]. It is currently unclear why these individuals, who we term Non-Demented with Alzheimer’s Neuropathology (NDAN), are resistant to the clinical manifestations of AD despite a significant burden of pathological lesions equivalent to what is normally found in comparably aged subjects with established AD. The recognized existence of NDAN individuals suggests that there are mechanisms by which the aging human brain may cope with cognitive dysfunction brought about by Aβ and NFT’s; and determining the protective molecular mechanisms involved in these resistant individuals could lead to the identification of novel targets for the development of effective therapeutic approaches [9]
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