Absence of amyloid β oligomers at the postsynapse and regulated synaptic Zn2+ in cognitively intact aged individuals with Alzheimer’s disease neuropathology

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.

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

“…In another study, low molecular weight SDSstable Ab oligomers were associated with the postsynaptic density in patients with Alzheimer dementia but not in nondemented HPCs. 76 Results are mixed for soluble Ab oligomers in cortical homogenates, but increased oligomers were reported in demented compared with HPC cases. 51 Our data come from synaptosome-enriched P-2 fractions with membrane cryopreservation, which would be expected to retain soluble oligomers; this is in contrast to typical homogenate samples, which are more dilute and represent multiple cell types and cellular compartments.…”

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…Overall, cell counting methods show that significant neuron loss does not occur during normal aging and changes are subtle and region‐specific (Burke & Barnes, 2006). A special case in successful aging is cognitive intact elderly with AD pathology, which are believed to have resistant mechanism for Aβ oligomers, and Aβ oligomers are absent from hippocampal postsynapses, while Zn 2+ levels are lower in such cases (Bjorklund et al, 2012). …”

Alzheimer’s disease and insulin resistance: translating basic science into clinical applications

“…Oligomers were recently observed at the postsynapse in AD hippocampi (39), and their levels are elevated in the brain and cerebrospinal fluid of AD patients (40)(41)(42). Interestingly, the absence of Aβ oligomers at the postsynapse was reported in cognitively intact elderly individuals whose brains presented amyloid deposits (39).…”