Rescue of neurogenesis and age-associated cognitive decline in SAMP8 mouse: role of transforming growth factor alpha

Abstract

Neuropathological aging is associated with memory impairment and cognitive decline, and affects several brain areas including the neurogenic niche of the dentate gyrus of the hippocampus (DG). In the healthy brain homeostatic mechanisms regulate neurogenesis in the DG to facilitate the continuous generation of neurons from neural stem cells (NSC). Nevertheless, aging reduces the number of activated neural stem cells, and diminishes the number of newly generated neurons. Strategies that promote neurogenesis in the DG may improve cognitive performance in the elderly resulting in the development of treatments to prevent the progression of neurological disorders in the aged population. Our work is aimed to discover targeting molecules to be used in the design of pharmacological agents to prevent the neurological effects of pathological aging. We study the effect of age on hippocampal neurogenesis using the SAMP8 mouse as a model of pathological aging. Thus, we show that in six-month-old SAMP8 mice, episodic and spatial memory are impaired, concomitantly the generation of neuroblasts and neurons is reduced and the generation of astrocytes is increased in this model. The novelty of our work resides in the fact that treatment of SAMP8 mice with a TGF-alpha targeting molecule, prevents the observed defects, positively regulating neurogenesis and improving cognitive performance. This compound facilitates the release of TGF-alpha in vitro and in vivo and activates signaling pathways initiated by this growth factor. We conclude that targeting the release of TGF-alpha may be the basis of pharmacological drugs to counteract the neurological effects of pathological aging.

Migratory Response of Cells in Neurogenic Niches to Neuronal Death: The Onset of Harmonic Repair?

“…Specifically, EOF2 activates novel PKCs [ 244 ], thus facilitating the release of neuregulin via ADAM17, whereas ER272 activates classical PKCs and facilitates the release of TGF-α [ 276 ], as described in Figure 2 . Moreover, in recent work, it has been demonstrated that ER272 prevents the neurogenic alterations and cognitive impairment found in the aging mouse model SAMP8 that are present characteristics of AD [ 281 ]. Therefore, compounds of this kind represent a promising pharmacological tool to promote neurogenesis and regeneration of the damaged brain.…”