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J Neurosci. 2014 Oct 1;34(40):13314-25. doi: 10.1523/JNEUROSCI.2848-14.2014.

The amyloid precursor protein controls adult hippocampal neurogenesis through GABAergic interneurons.

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Huffington Center on Aging, Department of Molecular and Human Genetics, and
Huffington Center on Aging, Department of Molecular and Human Genetics, and.
Huffington Center on Aging.
Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, and The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030.


Impaired neurogenesis in the adult hippocampus has been implicated in AD pathogenesis. Here we reveal that the APP plays an important role in the neural progenitor proliferation and newborn neuron maturation in the mouse dentate gyrus. APP controls adult neurogenesis through a non cell-autonomous mechanism by GABAergic neurons, as selective deletion of GABAergic, but not glutamatergic, APP disrupts adult hippocampal neurogenesis. APP, highly expressed in the majority of GABAergic neurons in the dentate gyrus, enhances the inhibitory tone to granule cells. By regulating both tonic and phasic GABAergic inputs to dentate granule cells, APP maintains excitatory-inhibitory balance and preserves cognitive functions. Our studies uncover an indispensable role of APP in the GABAergic system for controlling adult hippocampal neurogenesis, and our findings indicate that APP dysfunction may contribute to impaired neurogenesis and cognitive decline associated with AD.


Alzheimer's disease; GABAergic; adult neurogenesis; amyloid precursor protein; hippocampus; interneurons

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