UC San Diego

Alzheimer's Disease (AD) is a neurological disorder identified clinically by progressive memory loss and dementia and characterized pathologically by the presence of neuritic plaques, neurofibrillary tangles in the hippocampus and neocortex and neuronal degeneration in the basal forebrain cholinergic neurons. In vivo, these basal forebrain cholinergic neurons express the 75 kDa neurotrophin receptor (p75) and continue to rely on trophic support from their target regions in the adults animal. In vivo data has shown that expression of p75 and trkA are altered human patients with AD and in mouse models of AD. Furthermore, numerous studies have implicated a role for p75 in b-amyloid induced toxicity. Numerous studies have demonstrated that, in addition to binding b-amyloid, the p75 NTR mediates cytotoxicity induced by aggregated b-amyloid in a variety of different cellular systems. In contrast to the clearly demonstrated role of the p75 NTR in b-amyloid mediated cell death, more recent studies in human primary cortical neuron cultures suggest a neuroprotective role of the p75 NTR. Expression of the p75 NTR is also correlated with resistance to cytotoxicity induced by soluble oligomers of b-amyloid. In the present study, p75 neurotrophin receptor (p75NTR) null mutant mice were crossed with mice expressing one copy of hAPP751 containing both the Indiana and Swedish Familial Alzheimer's Disease mutations, under the control of the PDGFB promoter. Although at P0 p75NTR mutant mice carrying the PDGFB-hAPP751SWE, IND minigene are present with the expected frequency, we have observed unexpected postnatal lethality in approximately 70% of these mice by postnatal day 21. This lethality is associated with severe wasting and motor dysfunction, general developmental delay in multiple organ systems, sensory neuron loss, severe deficits in sympathetic innervation and changes in brain neuropathology. The early and striking phenotype in p75NTR mutant mice carrying the PDGFB-hAPP751SWE, IND minigene suggests that p75 may have a neuroprotective role in Alzheimer's Disease