Alzheimer's disease (AD) is an increasing health and social problem worldwide with prevalent cholinergic cell involvement. To reveal the details of the exact mechanisms, further preclinical studies in animals are needed. Our aim was to create a mouse model that represents the progression of AD with easy cholinergic manipulation. The 3xTg-AD and ChAT-Cre strains were crossbred. After serial genotyping, a colony, homozygote for all four genes (PSEN1, APPSwe, tauP301L and Cre; 3xAD-ChAT-Cre) was established. The presence of amyloid-β (Aβ) plaques and phosphor-Tau (pTau) aggregates was confirmed by immunohistochemistry. To test the functionality of the Cre enzyme, a stimulating DREADD virus (AAV8-hSyn-DIO-hM3Dq-mCherry) was injected unilaterally into the nucleus basalis magnocellularis, and clozapine-N-oxide-induced c-Fos activation was compared between the two hemispheres. Behavioral characterization was performed using the Y-maze, social discrimination (SDT), single pellet reaching (SPR), fox odor (FOT), and splash tests (ST). Food, water consumption and body weight change were investigated. Immunostaining and RNAscope confirmed the expression of Cre in ChAT-positive cells and the progressive appearance of pathological hallmarks (Aβ and pTau). The c-Fos activity was significantly increased in the virus-injected hemisphere. Compared with control mice, 3xAD-ChAT-Cre mice showed decreased locomotion (Y-maze, SDT, FOT), increased anxiety (FOT, ST) and weaker fine motor skills (SPR). In conclusion, newly created animals have a functional Cre recombinase enzyme in cholinergic cells. Additionally, the animals presented the pathophysiological hallmarks of AD in specific brain areas and maintained the typical behavioral alterations previously reported in 3xTg-AD mice. Thus, this strain seems to be appropriate for further studies.

Both seizures and epileptiform discharges have been reported in various amyloid plaque- forming mouse models of Alzheimer's disease (AD). These mice also show premature mortality possibly related to epileptic seizures. Yet, the relationship between epileptic manifestations and amyloid pathology remains elusive. We utilized deltaFosB as a marker for sustained neuronal hyperactivity to localize the epileptic focus and compared it with age and sex differences in premature mortality between APP/PS1, 5xFAD and wildtype littermate mice and epileptiform discharges (EDs) during sleep in cortex and hippocampus. APP/PS1 mice showed elevated FosB/deltaFosB (shortly FosB) staining in the dentate granule (DG) cells and CA1-CA3 pyramidal cells. These were also the origins of identified epileptiform discharges (EDs) in LFP recordings. APP/PS1 mice showed much higher premature mortality than 5xFAD mice, females more than males. FosB staining intensity in APP/PS1 mice was robustly elevated compared to wildtype mice and peaked at 3months of age. In contrast, FosB intensity in 5xFAD was lower than in wildtype mice at 1 and 3months of age, showing a modest elevation at 10months. In APP/PS1 mice between 1.5 and 3months of age, the DG amyloid load correlated positively with FosB intensity. Furthermore, the DG FosB intensity showed a positive correlation with the frequency of EDs during sleep. These findings suggest that FosB staining intensity can be used as a proxy for local epileptiform activity in AD model mice and help unveil cellular and molecular basis of AD related neuronal hyperactivity and epilepsy.

Pan-apoptosis and involvement of the inflammatory process are the hallmarks of Huntington's disease (HD). Inflammation currently represents one of the potential therapeutic targets for slowing and fighting the pathological phenotype of HD. The immunomodulatory properties of natural compounds, such as resveratrol, have been demonstrated in various disease models and human clinical trials. In the present study, we evaluated the neuroprotective and anti-inflammatory effects of the daily intranasal administration of resveratrol-conjugated gold nanoparticles in awake R6/2 mice, the genetic animal model of HD. Transgenic mice were treated daily with resveratrol-conjugated gold nanoparticles (0.1mg/kg/day) starting from 5weeks of age corresponding to the prodromal stage of the disease. After sacrifice, histological and immunofluorescence studies were performed. We found that resveratrol treated R6/2 mice survived longer and displayed a significant partial recovery of motor performance compared with R6/2 mice that received the nanoparticles with vehicle. Primary outcome measures such as striatal atrophy, neuronal intranuclear inclusions, and modulation of microglial reaction revealed a neuroprotective effect of resveratrol conjugated gold nanoparticles. Resveratrol provided a significant increase of neuroglobin, a neuroprotective globin, along with activated CREB and BDNF in the mice medium spiny neurons, accompanied by a down modulation of neuroinflammation, which, combined, might explain the beneficial effects observed in this model. Our findings showed that nanoparticles loaded with a specific compound which acts on the mutated protein intranuclear inclusions and inflammatory components may represent a valid therapeutic strategy in slowing down the symptoms of HD neurodegeneration.