Neuropeptide expression in mouse disease models

The role of neuropeptides and the significance of peptidergic mechanisms in neurodegenerative diseases are still relatively unexplored. In the periphery, nerve injury results in dramatic changes in the expression of neuropeptides (and other molecules). An interesting question is to what extent similar changes occur, and similar mechanisms operate, after lesions and/or degeneration in the brain. The purpose of this work is to study neuropeptides and other neuroactive molecules and their receptors in some mouse models for neurodegeneration using histochemical techniques.

PRION DISEASE MODELS. Mice intracerebrally inoculated with prions were studied at different time points. A decreased binding to NPY Y2 and NMDA receptors was seen in certain regions of the hippocampal formation, as well as an aberrant induction Of NPY mRNA in the CA3 pyramidal neurons, all changes from 110 days and onwards after prion inoculation. This is before behavioural symptoms appear. There were also increased levels of the inhibitory peptide galanin, npy and dynorphin in mossy fibers, whereas the excitatory CCK peptide was decreased.

ALZHEIMERS DISEASE MODELS. PDAPP and APP23 mice both overexpress human APP but with different mutations, leading to amyloid deposition. Pronounced changes were observed in the PDAPP and the APP23 mouse with regard to neuropeptides in the hippocampal formation and the ventral cortex, whereas the dorsolateral neocortex was comparatively less affected. Dystrophic and varicose peptide fibers containing galanin, NPY, CCK and/or enkephalin were commonly seen in close proximity to amyloid plaques. in addition generalised changes were observed in both models, such as increases of enkephalin and CCK in stratum lacunosum moleculare and Of NPY, enkephalin and dynorphin in mossy fibers/granule cells. in contrast CCK was decreased in mossy fibers in both types of mice. However, also differences were encountered between the two mouse models, in particular with regard to galanin.

THE MEGENCEPHALY MOUSE. The megencephaly mouse carries a spontaneous mutation in a potassium channel causing brain enlargement. The total brain volume, ventral cortex, hippocampal formation and cerebral cortex length were enlarged at eight weeks and onwards in the megencephaly mouse. Distinct disturbances in the expression Of BDNF, IGFBP 6 and several neuropeptides such as NPY, galanin and enkephalin were seen already at two weeks of age, that is before an obvious behavioral phenotype has been reported. The normal mouse brain appeared to grow for a longer period than hitherto assumed, that is up to eight weeks of age.

The results obtained in this thesis work show that neuropeptides are modulated, often in a similar way, in the brain of mouse models for Alzheimers disease and prion disease as well as in the megencephaly mouse. These changes are also reminiscent of the marked regulations of neuroactive molecules seen in peripheral neurons after nerve injury, suggesting that neurodegenerative disorders in the CNS may have some mechanisms in common with peripheral nerve injury. The significance of these alterations is not well understood, but it may reflect attempts to counteract degeneration by initiating protective and/or regenerative processes, as well as to attenuate excitation.

List of scientific papers

I. Diez M, Koistinaho J, DeArmond SJ, Camerino AP, Groth D, Caytano JC, Prusiner SB, Hokfelt T (1996). Aberrant induction of neuropeptide Y mRNA in hippocampal CA3 pyramidal neurones in scrapie-infected mice. Neuroreport. 7(12):1887-92.
https://pubmed.ncbi.nlm.nih.gov/8905686

II. Diez M, Koistinaho J, Dearmond SJ, Groth D, Prusiner SB, Hokfelt T (1997). Marked decrease of neuropeptide Y Y2 receptor binding sites in the hippocampus in murine prion disease. Proc Natl Acad Sci U S A. 94(24):13267-72.
https://pubmed.ncbi.nlm.nih.gov/9371835

III. Diez M, DeArmond SJ, Groth D, Prusiner SB, Hokfelt T (2001). Decreased MK-801 binding in discrete hippocampal regions of prion-infected mice. Neurobiol Dis. 8(4):692-9.
https://pubmed.ncbi.nlm.nih.gov/11493033

IV. Diez M, Groth D, DeArmond SJ, Prusiner SB, Hokfelt T (2003). Expression of neuropeptides in CD-1 and FVB mice infected with RML and ME7 prion. [Manuscript]

V. Diez M, Koistinaho J, Kahn K, Games D, Hokfelt T (2000). Neuropeptides in hippocampus and cortex in transgenic mice overexpressing V717F beta-amyloid precursor protein--initial observations. Neuroscience. 100(2):259-86.
https://pubmed.ncbi.nlm.nih.gov/11008166

VI. Diez M, Danner S, Sommer B, Staufenbiel M, Wiederhold K, Hokfelt T (2003). Neuropeptide alterations in the hippocampal formation and cortex of transgenic mice overexpressing APP with the Swedish double mutation (APP23). [Submitted]

VII. Diez M, Schweinhardt P, Peterson S, Lavebratt C, Schalling M, Hokfelt T, Spenger C (2003). MRI and in situ hybridization reveal early disturbances in brain size and gene expression in the megencephalic. (mceph/mceph) mouse. [Submitted]