Changes in bladder innervation in a mouse model of Alzheimer's disease

The aims of this study were to compare the structure of bladders from a transgenic mouse model of Alzheimer's disease with age matched control animals and to explore the idea that any structural differences might be related to functional bladder changes associated with the condition.

Two groups of mice were used. Transgenic animals in which the murine Amyloid Precursor Protein (APP) gene has been partly replaced by the human APP including both the Swedish and London mutations and that overexpress a mutant of the human Presenilin 1 gene (PS1M146L) driven by the PDGF promoter. The transgenic mice (App(SL)/PS1(M146L)) aged 24+/-3 months were used. The second group was an age matched control group of C57 black mice. The bladders from each group were isolated, fixed in 4% paraformaldehyde and prepared for immunohistochemistry. Antibodies to the vesicular acetylcholine transporter (VAChT) and neuronal nitric oxide synthase (nNOS) were used to identify neural structures.

Cholinergic nerves (VAChT(+)) were observed in the inner and outer muscle bundles of App(SL)/PS1(M146L) and control mice. No major differences were noted in the distribution of these fibres. In contrast, there was a distinct difference in the innervation of the sub-urothelial layer. In App1(SL)/PS1(M146L) mice there were numerous VAChT and nNOS positive fibres in sharp contrast to the paucity of similar nerves in control animals. VAChT and nNOS did not appear to co-localise in the same nerve fibres within the lamina propria. Pairs of nerve fibres, nNOS(+) and VAChT(+), were observed to be intertwined and run in close proximity. A particularly unusual feature of the App(SL)/PS1(M146L) mouse bladder was the presence of neurones within the bladder wall. These nerve cell bodies were seen in all App(SL)/PS1(M146L) mouse bladders. The neurones could be found singly or in small ganglion like groups of cells and were located in all layers of the bladder wall (sub-urothelium, in the lamina propria adjacent to the inner muscle and within the inner muscle and outer muscle layers). No nerve cells or small ganglia were noted in any of the control bladders studied.

There are structural differences in the bladders of App(SL)/PS1(M146L) mice compared to control animals. These differences are associated with sub-urothelial nerves which, because of their location, are likely to be sensory fibres. This may lead to a changed sensory processing from the App(SL)/PS1(M146L) bladders. The physiological role of the intra-mural neurones and ganglia is not known. It is speculated that they may be associated with peripheral motor/sensory mechanisms linked to the generation and modulation of sensation.