2024 American Academy of Neurology Abstract Website

Objective:

Investigating the contribution of the long non-coding RNA (lncRNA) Neat1 to memory deficits associated with normal aging and Alzheimer’s disease (AD).

Background:

Aging and AD are associated with profoundly altered gene expression profiles in the hippocampus; yet cell-type specific transcriptional changes underlying memory impairment are not well understood. The lncRNA Neat1 is increased in a highly cell-type dependent manner in the brain during normal aging and in AD. We previously demonstrated that during normal aging, a pancellular increase Neat1 drives repression of memory-critical genes while reducing Neat1 in dCA1 of the hippocampus is sufficient to improve hippocampus-dependent memory in aged mice. We hypothesized that cell-type specific changes in Neat1 contribute to age and AD-related changes in gene expression and subsequent memory impairment.

Design/Methods:

Expression of Neat1 and critical astrocyte related genes was quantified using Fluorescent in situ hybridization and qPCR in aged (18-24 month) C57BL/6 mice, as well as the hAPP-J20 mouse model of AD (4-6 months). Pancelluar or astrocyte specific knockdown of Neat1 using siRNA or AAV-shRNA respectively, was followed by a battery of cognitive and behavioral tasks to assess memory function.

Results:

We found that in both aged C57BL/6 mice and in the hAPP-J20 mouse model of AD, the proportion of astrocytes expressing Neat1 increases throughout the hippocampus. Moreover, we found that pancellular Neat1 knockdown using siRNA in dCA1 results in a decrease in astrocytes reactivity and improves cognitive function in the hAPP-J20 mouse. We also found that astrocyte-specific reduction of Neat1 is sufficient to rescue hippocampus-dependent memory in aged animals.

Conclusions:

These findings suggest the human APP transgene introduces an accelerated aging state in hippocampal astrocytes which then contributes to memory impairment. This study addresses an urgent need to understand cell-type specific mechanisms contributing to memory dysfunction in aging and AD.