## 4 Discussion
Among others, mice lacking endogenous PACAP show increased infarct volume in cerebral ischemia [68], increased damage in kidney ischemia/reperfusion injury [69], and increased ganglion cell death in retinal ischemia [70]. Moreover, regeneration after injuries is also slower, as it has been shown in axonal regeneration [71] and in callus formation following bone fracture [72]. These data support the protective role of endogenously expressed PACAP. Sporadic data support that even the partial lack of PACAP leads to increased injuries, but only a few papers have been published. [PERSON] et al. have found a similar degree of retinal ganglion cell loss in retinal injury to that observed in homozygous PACAP-deficient mice [73]. In the present study we found that the presenile systemic amyloidosis observed in homozygous mice [28] is similarly severe to that in heterozygous animals. This shows the importance of the endogenous PACAPergic system in protection against age-related degenerative conditions, summarized in Figure 4. Recently, PACAP has been found to counteract tau deposition in a model of Alzheimer's disease, highlighting the importance of the PAC1/PACAP system in the clearance of tau in the brain [74]. This observation, together with our data in amyloidosis, shows that PACAP can act against pathological protein depositions, leading to degenerative diseases. Figure 4: Summary of findings in PACAP HZ mice showing symptoms with different severity. In some reports, symptoms were between WT and KO mice in severity (**left** panel), while in others HZ mice were similar to WT animals (**middle** panel), and in some studies partial lack of PACAP was found to be sufficient to lead to severe symptoms, as observed in homozygous KO mice (**right** panel). Based on [28; 41; 68; 69; 70; 75]. Among the laboratory parameters, we found that total cholesterol, LDL, and HDL levels were significantly increased in HZ mice compared to WT animals. This is in accordance with our earlier findings in homozygous mice, where we described a similar tendency in both young and aging groups. Although very few and partially contradicting data are available, PACAP has been implicated in several metabolic processes, including lipid metabolism. Among others, the early postnatal death of PACAP-deficient mice was shown to be associated with disturbed lipid metabolism, where authors found elevated serum triglyceride and cholesterol levels in PACAP null mice [76]. In addition, PACAP has been shown to increase adipocyte lipolysis [77; 78; 79], free fatty acid, and triglyceride levels, but no change was observed in cholesterol after infusion and bolus injection in dogs [80]. These and other related effects of PACAP in inflammatory processes may be in the background for the described accelerated atherosclerosis found in PACAP/Apolipoprotein E-deficient mice [81], although no change in cholesterol levels were found in these mice. PACAP was also found to ameliorate lipid metabolism and inflammation in fatty liver [82]. Total blood count showed no major differences between WT and HZ mice, but data from our young mice showed minor but statistically significant differences in parameters reflecting formation and maturation of red blood cells and platelets. Reticulocyte as well as nucleated red blood cell count was lower, while mean corpuscular hemoglobin concentration was higher, and plateletcrit was found to be slightly increased in HZ mice. Although we cannot draw final conclusions from these data, PACAP has already been demonstrated to be involved in hematopoiesis. The very limited data from the literature show, for example, that PACAP is involved in hematopoietic progenitor cell proliferation [18] and in megakaryocyte maturation [83; 84].