. In vivo restoration of physiological levels of truncated TrkB.T1 receptor rescues neuronal cell death in a trisomic mouse model. Neuron. 2006 Jul 6;51(1):21-8. PubMed.

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  1. The articles by Dorsey and colleagues and Mobley's group (see Salehi et al., 2006) are particularly relevant to recent findings that our group has generated using human autopsy material to investigate the neurobiological mechanisms underlying cholinotrophic basal forebrain dysfunction during the progression of AD (see review by Counts and Mufson, 2004). Findings derived from autopsy material harvested from people with a premortem clinical diagnosis of non-cognitive impairment, mild cognitive impairment, and AD revealed that subtle alterations or shifts in the balance between proNGF and the high-affinity TrkA receptor for NGF may play a crucial role in the survival of cholinergic neurons during the progression of AD. Shifts in the balance between NGF and its high-affinity receptor may dysregulate pro-survival and initiate apoptotic signaling leading to cholinergic basal forebrain neuronal death. The findings of Dorsey et al. suggest that relatively small imbalances in the physiological levels of TrkB receptor isoforms affect neuronal survival by altering BDNF-induced pro-survival signaling. Together, these findings suggest that the success of exogenous neurotrophin therapy for neurological diseases such as AD may depend upon a fine balance between neurotrophin and receptor interactions.

    Several years ago, it was demonstrated that there is a reduction in retrogradely transported NGF within cholinergic neurons of the nucleus basalis in AD (Mufson and Kordower, 1997). The article by Salehi et al. provides information that APP acts to reduce the retrograde transport of NGF in the cholinergic cortical projection neurons, a process important for their survival and relevant to their selective vulnerability in AD. Moreover, this study links the amyloid hypothesis to cholinergic basal forebrain degeneration and their ultimate demise in AD.

    Together, these observations provide evidence of the complex nature of neurotrophin/receptor as well as defects in neurotrophin retrograde transport as putative functional deficits which ultimately play a role in neuronal survival and death in various disease states. Interestingly, Costantini et al. (2005) showed that a TrkA-to-p75NTR molecular switch activates amyloid-β expression during aging. This novel information demonstrates that subtle shifts in neurotrophin receptor balance not only can affect neuron survival in neurological disease but also during the normal aging process.

    References:

    . A TrkA-to-p75NTR molecular switch activates amyloid beta-peptide generation during aging. Biochem J. 2005 Oct 1;391(Pt 1):59-67. PubMed.

    . The role of nerve growth factor receptors in cholinergic basal forebrain degeneration in prodromal Alzheimer disease. J Neuropathol Exp Neurol. 2005 Apr;64(4):263-72. PubMed.

    . In vivo restoration of physiological levels of truncated TrkB.T1 receptor rescues neuronal cell death in a trisomic mouse model. Neuron. 2006 Jul 6;51(1):21-8. PubMed.

    . Nerve growth factor in Alzheimer's disease: defective retrograde transport to nucleus basalis. Neuroreport. 1995 May 9;6(7):1063-6. PubMed.

    . Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron. 2006 Jul 6;51(1):29-42. PubMed.

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