Augmenting neurogenesis rescues memory impairments in Alzheimer’s disease

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Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, and plays important roles in the consolidation of information from short-term memory to long-term memory, and in spatial memory that enables navigation. enter image description here

In the human, adult neurogenesis has been shown to occur at low levels, and in only three regions of the brain: the lateral ventricles, the amygdala and the hippocampus.

Hippocampal neurogenesis is impaired in Alzheimer’s disease patients, yet, it is unknown whether new neurons play a causative role in memory deficits. Dans un nouvel article Rachana Mishra, Orly Lazarov and colleagues show that immature neurons were actively recruited into the engram following a hippocampus-dependent task. An engram is the association of neuronal physical areas to external stimulus.

To examine whether the augmentation of adult hippocampal neurogenesis rescues learning and memory deficits in FAD, they generated four mouse model of familial Alzheimer disease with inducible neurogenesis. Bax gene deletion is known to enhance the survival of neural progenitor cells and led to increased neurogenesis. Bax belongs to the BCL2 family members which act as anti- or pro-apoptotic regulators, as usual, involved in a wide variety of cellular activities.

Targeted augmentation of neurogenesis in familial Alzheimer’s disease mice restored the number of new neurons in the engram, the dendritic spine density, and the transcription signature of both immature and mature neurons, ultimately leading to the rescue of memory. enter image description here

Chemogenetic inactivation of immature neurons following enhanced neurogenesis in Alzheimer’s disease, reversed mouse performance, and diminished memory. Notably, Alzheimer’s disease-linked App, ApoE, and Adam were of the top differentially expressed genes in the engram.

Collectively, these observations suggest that defective neurogenesis contributes to memory failure in Alzheimer’s disease.

First is the direct evidence that immature neurons in the DG play a role in hippocampus-dependent memory engram in wild-type and FAD mice.

Second, impairments in hippocampal neurogenesis cause defective engram formation in FAD and underlie memory deficits.

Third, an increasing level of neurogenesis rescues memory by restoring the engram.

Fourth, immature neurons are required for proper memory formation in FAD.

Fifth, augmenting neurogenesis rescues deficits in spine density in both immature and mature engram neurons in the DG of FAD mice.

Sixth, augmenting neurogenesis modulates the profile of immature and mature engram neurons in the DG to resemble the transcription profile of engram cells in wild-type mice.

Seventh, AD-linked signals, particularly App, Apoe, and Adam, play a role in the engram and are modulated following augmentation of neurogenesis and rescue of memory.

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