Genotype Load Modulates Amyloid Burden and Anxiety-Like Patterns in Male 3xTg-AD Survivors despite Similar Neuro-Immunoendocrine, Synaptic and Cognitive Impairments

Abstract

The wide heterogeneity and complexity of Alzheimer’s disease (AD) patients’ clinical profiles and increased mortality highlight the relevance of personalized-based interventions and the need for end-of-life/survival predictors. At the translational level, studying genetic and age interactions in a context of different levels of expression of AD-genetic-load can help to understand this heterogeneity better. In the present report, a singular cohort of long-lived (19-month-old survivors) heterozygous and homozygous male 3xTg-AD mice were studied to determine whether their AD-genotype load can modulate the brain and peripheral pathological burden, behavioral phenotypes, and neuro-immunoendocrine status, compared to age-matched non-transgenic controls. The results indicated increased amyloid precursor protein (APP) levels in a genetic-load-dependent manner but convergent synaptophysin and choline acetyltransferase brain levels. Cognitive impairment and HPA-axis hyperactivation were salient traits in both 3xTg-AD survivor groups. In contrast, genetic load elicited different anxiety-like profiles, with hypoactive homozygous, while heterozygous resembled controls in some traits and risk assessment. Complex neuro-immunoendocrine crosstalk was also observed. Bodyweight loss and splenic, renal, and hepatic histopathological injury scores provided evidence of the systemic features of AD, despite similar peripheral organs’ oxidative stress. The present study provides an interesting translational scenario to study further genetic-load and age-dependent vulnerability/compensatory mechanisms in Alzheimer’s disease.

Crosstalk of Alzheimer’s disease-phenotype, HPA axis, splenic oxidative stress and frailty in late-stages of dementia, with special concerns on the effects of social isolation: A translational neuroscience approach

“…In these 18-month-old cohorts, no differences were found, but a trend to increase in 3xTg-AD females and the isolated subgroup correlated with those in spleen organometrics. The higher frailty scores were observed in the integument and muscular-skeletal systems, such as alopecia, loss of whiskers, and dermatitis, which are the more common frailty clinical presentations in aged mice ( Pettan-Brewer and Treuting, 2011 ; Muntsant and Giménez-Llort, 2021 ).…”

“…Total glutathione (GSH) levels were assayed by the enzymatic recycling method by monitoring the change in absorbance at 412 nm adapted to 96-well plates. Glutathione reductase (GR) enzymatic activity was assessed following the oxidation of NADPH spectrophotometrically at 340 nm for 300 s. For the GPx activity, the reaction was followed spectrophotometrically by the decrease of the absorbance at 340 nm for 300 s ( Muntsant and Giménez-Llort, 2021 ).…”

Memory Enhancement with Kynurenic Acid and its Mechanisms in Neurotransmission

“…Preclinical translational animal studies play a major role in neuroscience research to understand the roles of neuropeptides, neurohormones, and endogenous biomolecules in the normal function of human life such as cognition, emotion, and social interaction, and in pathological alterations developing into neurological and psychiatric disorders [82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97]. Various bioactive molecules are synthesized in the Try-KYN metabolic system.…”

EK100 and Antrodin C Improve Brain Amyloid Pathology in APP/PS1 Transgenic Mice by Promoting Microglial and Perivascular Clearance Pathways

“…Animal models were first used to understand AD mechanisms, but above all, they were used to test drugs preventing cognitive deficits for therapeutic interventions. However, none of the current developed animal models is able to entirely reproduce the AD pathology, since the deposition of Aβ and its consequence are not limited to the central nervous system [ 6 , 7 , 8 ].…”