Drug Development

Alzheimers Dement. 2024 Dec:20 Suppl 6:e093081. doi: 10.1002/alz.093081.

Abstract

Background: Apolipoprotein E4 (apoE4) has been identified as the major genetic risk factor for late onset Alzheimer's disease (AD). Our lab has demonstrated that chronic administration of Aβ12-28P, a synthetic peptide that blocks apoE4/Aβ binding, in middle-aged transgenic AD mice significantly ameliorates pathology progression, resulting in reduced Aβ plaques deposition and cerebral amyloid angiopathy (CAA) along with improved memory and cognition. However, whether blocking apoE4/Aβ interaction by Aβ12-28P also has an ameliorating effect on the neuronal and cognitive function of old AD mice where Aβ pathology has been extensively developed remains unknown.

Method: Geriatric SwDI/APOE4 mice (18-24 months old) were intraperitoneally injected daily with Aβ12-28P, while control mice received only saline. Behavioral tests including anxiety in open field, locomotor activity, T-maze, object recognition, and radial arm maze were performed 2 hours post-injection to assess the acute effect of Aβ12-28P. After 3 weeks of behavioral testing with daily treatment, acute hippocampal slices were prepared and subjected to in vitro physiology experiments to evaluate long-term potentiation (LTP) of Schaffer collateral input to CA1. On the recording day Aβ12-28P or saline was injected 2 hours before slice preparation.

Result: Acute Aβ12-28P treatment resulted in significant cognitive improvement. While the treated mice did not show differences in locomotor activity, significantly enhanced cognitive performances were observed, including improved performance in one-day T-maze test (n = 10/group, p = 0.0005), one-day novel object recognition test (n = 6/group, p = 0.018), and multiple-days radial arm maze test (n = 8-9/group, p = 0.0008). Aβ12-28P administration also significantly reduced anxiety in open field (n = 6/group, p = 0.0081). We further compared the hippocampal Schaffer collateral LTP in slices from Aβ12-28P-treated versus non-treated mice. Slices from the treated animals showed significantly enhanced LTP (n = 9-10/group, p < 0.0001), suggesting rescued synaptic plasticity.

Conclusion: These results suggest that acute Aβ12-28P administration blocking apoE/Aβ binding rescues synaptic plasticity and cognitive decline in old AD mice where extensive Aβ pathology has been developed. Our finding opens the possibilities to apply the strategy of targeting apoE/Aβ interaction for alleviating advanced-stage AD symptoms in addition to ameliorating Aβ deposition during AD progression.