The neuronal Shc adaptor in Alzheimer’s Disease

Preserving cognitive functions from age-related decline and Alzheimer’s Disease (AD) represents one of the major challenges of modern Neuroscience. However, we are currently unable to counteract the neurodegenerative process at an early stage, a prerequisite to minimize structural damage and recover learning and memory functions. Reduced neurotrophic support by Nerve Growth Factor (NGF) and Brain Derived Neurotrophic Factor (BDNF) to the basal forebrain system has been extensively shown to cause cholinergic related cognitive dysfunction and neurogenesis alterations, thus contributing to AD aetiopathogenesis. Neurotrophin binding to the specific tyrosine kinase receptor (TrkA for NGF and TrkB for BDNF) allows phosphorylation and docking of early Trks adaptors shc (Src homology and collagen homology), thus promoting neuronal survival, phenotype maintenance and synaptic activity. Shc family is made of several isoforms sharing phosphotyrosine binding domains consisting of the N-terminal phosphotyrosine-binding (PTB) and the C-terminal Srchomology2 (SH2) sequences, and is involved in brain development/functions, cancer and immunity. The neuronal Shc isoform C (N-Shc), also known as ShcC/Rai/Shc3/Shk, is envisaged as an elective molecular target to achieve brain neuroprotection in AD. The N-Shc protein evolutionary correlates with vertebrate brain development. In line with a major role in central nervous system functions, N-Shc is implicated in brain and retinal development, as well as in adult neurogenesis [1,2]. It is expressed as two 55 (p55) and 69 (p69) kDa isoforms specifically in post mitotic CNS neurons, and it is topographically enriched in the forebrain [3]. N-Shc initiates PI3 kinase-dependent sustained survival/differentiation, potentiates MAPK signaling and hampers JNK activation, being antiapoptotic [4]. N-Shc activation exerts a crucial role in Long Term Potentiation (LTP) and is neuroprotective against aging-associated diseases, like ischemia [5] and oxidative stress [6]. In line with a major neuroprotective role of the signaling adaptor protein, a reduction of NShc protein and mRNA have been reported in brain aging, and AD [6]. Also, we observed a perturbation in the Shc pathway, with a specific down regulation of NShc phosphorylation in the forebrain of Tg2576 mice, a diffuse mouse model of AD (D). In line with this, N-Shc Editorial