Alzheimer’s disease (AD) is often not diagnosed until its late stages, which is predominately characterized by neurodegeneration. Treatments are largely ineffective for AD, and one explanation is that once the disease is recognized pathology is irreversible. Thus, recognizing and characterizing early AD is of paramount importance (Gidyk, Deibel, Hong, & McDonald, 2015).

Roy and colleagues (2016) recently investigated the mechanisms underlying memory in a mouse model of early AD. The authors concluded that the memory impairment in early AD is due to an inability to retrieve the memory and targeted stimulation of the hippocampal (HPC) cells involved in a specific memory to facilitate natural retrieval of that memory. A transgenic mouse model of AD was used that only displayed amyloid plaques in the dentate gyrus (DG) region of the HPC and medial entorhinal cortex at 9 and not 7 months of age. While both ages had impaired long-term memory (LTM; 24-h) of single context fear conditioning (CFC), only 7-month-old animals had normal short-term memory (STM; 1-h). Interestingly, although the density of DG cells was normal in the 7-month-old mice, these animals had decreased cFos (a marker of neuronal activity)-labeled DG cells compared to control mice after the LTM test. The authors concluded that the 7-month-old animals represented early AD (henceforth referred to as early AD mice).

The authors have previously reported that a population of DG cells representing a specific memory (engram) can be identified via transgenic modifications and then manipulated with optogenetics (Liu et al., 2012). In the current study, the authors created early engram AD mice that also had impaired LTM. Amazingly, when the DG engram was optogenetically activated in a novel context these mice displayed freezing behavior similar to control animals. The authors replicated this effect in several different transgenic mouse models. The authors concluded that the LTM impairment in these early AD mice was due to failure to retrieve the memory.

Next the authors delved deeper into the nature of the engram cells. While neurogenesis and functional connectivity of the DG engram cells was normal, only the DG cells that were part of the engram had decreased dendritic spine density. The authors hypothesized that induction of long-term potentiation (LTP) in the DG engram cells would restore spine density and thus rescue memory. LTP was induced in the DG engram cells by optogenetically stimulating entorhinal cortex perforant path cells that terminated in these DG cells. Memory recall was tested 48-h after this manipulation without any optogenetic manipulations. This procedure restored spine density of DG engram cells and rescued the fear memory (replicated for other types of memory) for up to 6 days after the optical LTP induction. This effect was dependent on inducing LTP in only the engram cells, as induction of LTP in a large population of perforant path terminals in the DG did not rescue memory. To ensure that the induction of LTP in the DG engram cells was not inducing LTP in other DG cells and thus influencing memory retrieval, they developed an engram-specific virus that would only ablate the DG engram cells. Ablation of the DG engram cells after induction of LTP impaired memory. These data suggest that LTP induction in only the DG engram cells facilitates natural memory retrieval. The authors conclude that, in contrast to previous reports, the memory impairment in early AD is due to a failure to retrieve encoded information rather than an inability to encode that information.

There is a significant amount of excitement around this work, particularly from a technical point of view, but the work also has conceptual, theoretical, and applied implications. Our goal is to provide some alternative views of the work and place it in the context of the field.