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.
Highlights
Whereas cognitive dysfunction defines the diagnosis of the core clinical symptoms, neuropsychiatric symptoms (NPS) [3], called Behavioral and Psychological Symptoms of Dementia (BPSD), are observed in 90% of patients
The singular cohort of long-lived (19-month-old survivors) heterozygous and homozygous male 3xTg-Alzheimer’s disease (AD) mice studied here indicates that the AD-genotype load modulates the brain and peripheral pathological burden, behavioral phenotypes, and neuroimmunoendocrine status, compared to age-matched non-transgenic controls
The main findings pointed at the non-linear impact of genetic load in the different dimensions studied
Summary
Alzheimer’s disease (AD) is the leading cause of dementia, one of the principal causes of disability in late adulthood. It is a multi-factorial disorder caused by the interaction of biological, environmental factors, where age-related changes play a determinant role [1]. The broad array of NPS include agitation, anxiety, verbal, or physical aggression, sundowning behavior, wandering, depression, challenging and disruptive behaviors, hallucinations, among other alterations [4]. These NPS are highly associated with the burden of disease, lower quality of life and caregiver burnout [5], and earlier institutionalization [6]
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