Survival Bias and Crosstalk between Chronological and Behavioral Age: Age- and Genotype-Sensitivity Tests Define Behavioral Signatures in Middle-Aged, Old, and Long-Lived Mice with Normal and AD-Associated Aging

Abstract

New evidence refers to a high degree of heterogeneity in normal but also Alzheimer’s disease (AD) clinical and temporal patterns, increased mortality, and the need to find specific end-of-life prognosticators. This heterogeneity is scarcely explored in very old male AD mice models due to their reduced survival. In the present work, using 915 (432 APP23 and 483 C57BL/6 littermates) mice, we confirmed the better survival curves in male than female APP23 mice and respective wildtypes, providing the chance to characterize behavioral signatures in middle-aged, old, and long-lived male animals. The sensitivity of a battery of seven paradigms for comprehensive screening of motor (activity and gait analysis), neuropsychiatric and cognitive symptoms was analyzed using a cohort of 56 animals, composed of 12-, 18- and 24-month-old male APP23 mice and wildtype littermates. Most variables analyzed detected age-related differences. However, variables related to coping with stress, thigmotaxis, frailty, gait, and poor cognition better discriminated the behavioral phenotype of male APP23 mice through the three old ages compared with controls. Most importantly, non-linear age- and genotype-dependent behavioral signatures were found in long-lived animals, suggesting crosstalk between chronological and biological/behavioral ages useful to study underlying mechanisms and distinct compensations through physiological and AD-associated aging.

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

“…In this sense, our laboratory has described convergence of profiles in the context of poor aging from 12 to 18 months of age as part of the complexity of age-related scenarios and heterogeneity among all populations, including both wildtype mice and 3xTg-AD mice [19,50,53]. The survival of very old 3xTg-AD mice points to the existence of distinct brain and systemic physiological protective mechanisms for AD-pathology besides those that may exist in normal aging [50,70].…”

Modulation of Neurolipid Signaling and Specific Lipid Species in the Triple Transgenic Mouse Model of Alzheimer’s Disease

“…Moreover, synaptic dysfunction and long-term potentiation deficits are already apparent at this age, although no extracellular Aβ deposits are localized at the hippocampal region. Moreover, behavioral age is an important factor in this 3xTg-AD mouse model [22,23]. Regarding the neurochemical alterations observed in AD patients, cholinergic neurotransmission seems to be one of the most characteristic alterations, including the loss of cholinergic neurons at the basal nucleus of Meynert in AD patients [24].…”

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.…”