Article Summary Task

Richetin (2015). Genetic Manipulation of adult-born hippocampal neurons rescues memory in a mouse model of Alzheimer’s disease. Brain: A Journal of Neurology, 138; 440-455.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterised by progressive memory loss and cognitive deficits often seen in the elderly. Recent research has suggested that adult hippocampal neurogenisis is affected during the progression of the disease. In a transgenic mice model of AD, this altered pattern of neurogenisis is seen to appear early on in the development of the condition; suggesting that endogenous enhancement of neurogenisis may be a possible therapeutic intervention leading to improved hippocampal function. The present study hypothesised that enhancing neurogenisis would improve functional plasticity in the hippocampus thus restoring cognitive deficits in the mice.

Intra-hippocampal injections of retoviral vectors; Neurog2, Neurod1 and Neurod2 were administered to three-month-old wild-type mice. Tissue analysis found that transcription factor Neurod1 increased the number of new granule neurons in the hippocampus as well as increasing synaptic connectivity and the integration of new neurons within the hippocampal network. As new hippocampal neurons contribute to spatial memory processes in a healthy mouse brain, supplying the AD brain with new, highly excitable granule neurons may improve hippocampal cognitive function.

To test this hypothesis a transgenic mice model of AD and aged matched controls were tested before and after R-Neurod1 administration in two independent object location tasks. Before viral administration, both transgenic mice and controls matched in their exploratory behaviour towards the objects indicative that both genotypes exhibited the same exploratory drive. 24 hours later mice were exposed to a memory test which involved finding the displaced item in a novel location. Controls showed preference towards the displaced item, whereas AD mice showed no exploratory preference, thus indicating that AD mice were unable to discriminate the novel from familiar location.

Mice from each genotype were randomly divided into two groups and received either a control or the R-Neurod1 vector. When the task was repeated 21 days after injection, control mice and mice in the AD condition injected with R-Neurod1 showed exploratory preference to the displaced object. AD mice injected with the control vector showed no preference. This suggests memory impairment in the AD experimental group was restored and that the AD mice were now able to discriminate the novel location from the familiar one.

These findings grant evidence to suggest that manipulation of the connectivity of adult hippocampal neural progenitors through forced expression of Neurod1 may open up the possibility for the treatment of the hippocampal dysfunction associated with neurodegenerative diseases such as Alzheimer’s disease.

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