Short-Term Pharmacological Induction of Arterial Stiffness and Hypertension with Angiotensin II Does Not Affect Learning and Memory and Cerebral Amyloid Load in Two Murine Models of Alzheimer's Disease.

Given the unprecedented rise in the world's population, the prevalence of prominent age-related disorders, like cardiovascular disease and dementia, will further increase. Recent experimental and epidemiological evidence suggests a mechanistic overlap between cardiovascular disease and dementia with a specific focus on the linkage between arterial stiffness, a strong independent predictor of cardiovascular disease, and/or hypertension with Alzheimer's disease. In the present study, we investigated whether pharmacological induction of arterial stiffness and hypertension with angiotensin II (1 µg·kg-1·min-1 for 28 days via an osmotic minipump) impairs the progression of Alzheimer's disease in two mouse models (hAPP23+/- and hAPPswe/PSEN1dE9 mice). Our results show increased arterial stiffness in vivo and hypertension in addition to cardiac hypertrophy after angiotensin II treatment. However, visuospatial learning and memory and pathological cerebral amyloid load in both Alzheimer's disease mouse models were not further impaired. It is likely that the 28-day treatment period with angiotensin II was too short to observe additional effects on cognition and cerebral pathology.

Age-related cognitive decline in spatial learning and memory of C57BL/6J mice.

During the last decades, most of the preclinical neurodegenerative research was performed in mouse models of amyloidosis, tauopathies or α-synucleinopathies preferentially maintained on a C57BL/6J background. However, comprehensive neurobehavioural data from C57BL/6J mice outlining the critical point of spontaneous cognitive decline are incomplete. In this study, we aimed for the neurobehavioural phenotyping of hippocampus-dependent spatial learning and memory of aging C57BL/6J mice. Neurobehavioural phenotyping was performed by means of a Morris Water Maze (MWM) and a Novel Object Recognition (NOR) test. MWM measurements revealed signs of age-related memory loss in C57BL/6J animals from the age of 6 months onward. The NOR assessment strengthened latter finding by decreasing discrimination indexes (DI) and recognition indexes (RI) starting from the age of 6 months. Taken together, these findings contribute to the current knowledge of spontaneous cognitive behaviours of this perhaps most widely used mouse strain and serve as a benchmark for dementia mouse models to distinguish spontaneous from pathological neurodegenerative behaviour.

Long-Term Pharmacological Inhibition of the Activity of All NOS Isoforms Rather Than Genetic Knock-Out of Endothelial NOS Leads to Impaired Spatial Learning and Memory in C57BL/6 Mice.

Increasing epidemiological and experimental evidence points to a link between arterial stiffness and rapid cognitive decline. However, the underlying mechanism linking the two diseases is still unknown. The importance of nitric oxide synthases in both diseases is well-defined. In this study, we introduced arterial stiffness in both genetic (eNOS-/-, endothelial nitric oxide synthase knockout) and pharmacological (N(G)-nitro-L-arginine methyl ester (L-NAME) treatment) NO dysfunction models to study their association with cognitive decline. Our findings demonstrate that the non-selective inhibition of NOS activity with L-NAME induces cardiac dysfunction, arterial stiffness, and a decline in hippocampal-dependent learning and memory. This outcome demonstrates the importance of neuronal NOS (nNOS) in both cardiovascular and neurological pathophysiology and its potential contribution in the convergence between arterial stiffness and cognitive decline.

Serum Corticosterone and Insulin Resistance as Early Biomarkers in the hAPP23 Overexpressing Mouse Model of Alzheimer's Disease.

Increasing epidemiological evidence highlights the association between systemic insulin resistance and Alzheimer's disease (AD). As insulin resistance can be caused by high-stress hormone levels and since hypercortisolism appears to be an important risk factor of AD, we aimed to investigate the systemic insulin functionality and circulating stress hormone levels in a mutant humanized amyloid precursor protein (APP) overexpressing (hAPP23+/-) AD mouse model. Memory and spatial learning of male hAPP23+/- and C57BL/6 (wild type, WT) mice were assessed by a Morris Water Maze (MWM) test at the age of 4 and 12 months. The systemic metabolism was examined by intraperitoneal glucose and insulin tolerance tests (GTT, ITT). Insulin and corticosterone levels were determined in serum. In the hippocampus, parietal and occipital cortex of hAPP23+/- brains, amyloid-beta (Aß) deposits were present at 12 months of age. MWM demonstrated a cognitive decline in hAPP23+/- mice at 12 but not at 4 months, evidenced by increasing total path lengths and deteriorating probe trials compared to WT mice. hAPP23+/- animals presented increased serum corticosterone levels compared to WT mice at both 4 and 12 months. hAPP23+/- mice exhibited peripheral insulin resistance compared to WT mice at 4 months, which stabilized at 12 months of age. Serum insulin levels were similar between genotypes at 4 months of age but were significantly higher in hAPP23+/- mice at 12 months of age. Peripheral glucose homeostasis remained unchanged. These results indicate that peripheral insulin resistance combined with elevated circulating stress hormone levels could be potential biomarkers of the pre-symptomatic phase of AD.