The basal forebrain cholinergic neurons (BFCNs) are implicated in high cognitive processes such attention and memory as they project to regions like the cortex and the hippocampus. These neurons express high amounts of the p75 neurotrophin receptor (p75NTR) during their whole life, nevertheless, the role that the receptor plays in them is not fully understood. During the experimental work of this thesis, the role that p75NTR plays during ageing and the role of the proteolytic processing of p75NTR have been studied. The first objective was achieved using a mouse model of accelerated senescence, SAMP8. This mouse model was crossed with the knock-out of p75NTR, obtaining the SAMP8-p75NTR-/- mouse. The results showed how at young ages (2 months) there is an increase in the number of BFCNs in SAMP8-p75NTR-/- compared to SAMP8-p75NTR+/+ mice. However, in adult mice (6 months) and aged mice (10 months) the number of cholinergic neurons between SAMP8-p75NTR+/+ and SAMP8-p75NTR-/- are the same, indicating a cholinergic neuronal loss. In addition, the same result has been reported in the C57BL/6 background. The number of cholinergic neurons were quantified at postnatal day 16 and 2, 10 and 24 months. The results showed an increase in the number of BFCNs at 16 days old in C57BL/6-p75NTR-/- mice compared to C57BL/6-p75NTR+/+ animals. Nevertheless, the levels were reduce at 2, 10 and 24 months in C57BL/6-p75NTR-/- mice. The reduction in the number of cholinergic neurons is accompanied by a reduction in the levels of specific cholinergic markers such as: ChAT, acetylcholine and Acly in SAMP8-p75NTR-/- mice at 6 months. The results showed that neuronal cholinergic death is not due to a reduction in the oxidative stress response, since the SAMP8-p75NTR+/+ and the SAMP8-p75NTR-/- have the same oxidative response at 6 months of age. Nonetheless, SAMP8-p75NTR-/- mice present different levels in key enzymes of the cholesterol synthesis and endocytic pathway. Indicating that in the SAMP8-p75NTR-/- mice there might be a deregulation in the homeostasis of cholesterol explaining why cholinergic neurons degenerate. In addition, the cholinergic neuronal loss has a spatial memory effect as the SAMP8-p75NTR-/- mice perform worst the Y-maze test at 6 months compared to 2 months. The p75NTR is proteolytically cleaved by the α-secretase generating the C-terminal domain, which is further cleaved by the γ-secretase. To study the effect of the p75NTR cleavage, primary cultures of cholinergic neurons were used and the γ-secretase was chemically inhibited. The addition of CE (a γ-secretase inhibitor) to the cholinergic neurons specifically increases their complexity and length. Furthermore, it was seen that this effect is p75NTR-dependent as in p75NTR-/- cultures the effect disappears. In addition, we have proved that the increase in complexity is through the inhibition of the RhoA protein, a cytoskeleton regulatory protein. These results were confirmed in organotypic brain slices, as the addition of CE causes the same effect, an increase in the complexity of cholinergic neurons. Furthermore, in mouse models in which the γ-secretase is genetically inhibited, there is an increase in acetylcholinesterase fibres in the cortex and hippocampus, places of innervation of cholinergic neurons. This is an indication of increased complexity in a in vivo situation. All together the results of this thesis have amplified the knowledge of the p75NTR in the basal forebrain cholinergic neurons. Demonstrating a cholinergic dependence of the receptor during adulthood and ageing, probably to a cholesterol homeostasis deregulation. Moreover, the accumulation of p75NTR-CTF, increases cholinergic complexity, indicating another role of p75NTR in the cholinergic neurons regulating their morphology.
