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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions1. Memory decline in the early stages of AD is mostly limited to episodic memory, for which the hippocampus has a crucial role2. However, it has been uncertain whether the observed amnesia in the early stages of AD is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early AD, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are used, revealing a retrieval, rather than a storage impairment. Before amyloid plaque deposition, the amnesia in these mice is age-dependent3-5, which correlates with a progressive reduction in spine density of hippocampal dentate gyrus engram cells. We show that optogenetic induction of long-term potentiation at perforant path synapses of dentate gyrus engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of dentate gyrus engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in the early stages of AD.
AD is the most common cause of brain degeneration, and typically begins with impairments in cognitive functions1. Most research has focused on understanding the relationship between memory impairments and the formation of two pathological hallmarks seen in the late stages of AD: extracellular amyloid plaques and intracellular aggregates of tau protein1,2. The early phases of AD have received relatively less attention, although synaptic phenotypes have been identified as major correlates of cognitive impairments in both human patients and mouse models3,6. Several studies have suggested that the episodic memory deficit of AD patients is due to ineffective encoding of new information7-9. However, since the cognitive measures used in these studies rely on memory retrieval, it is not possible to discriminate rigorously between impairments in information storage and disrupted retrieval of stored information. This issue has an important clinical implication: if the amnesia is due to retrieval impairments, memory could be restored by technologies involving...