Long-term Treatment with Low-Dose Caffeine Worsens BPSD-Like Profile in 3xTg-AD Mice Model of Alzheimer’s Disease and Affects Mice with Normal Aging

Abstract

Coffee or caffeine has recently been suggested as prophylaxis for dementia. Although memory problems are hallmarks of Alzheimer’s disease, this dementia is also characterized by neuropsychiatric symptoms called Behavioral and Psychological Symptoms of Dementia (BPSD). The impact of preventive/therapeutic strategies on both cognitive and non-cognitive symptoms can be addressed in the 3xTg-AD mice, since they exhibit cognitive but also BPSD-like profiles. Here, we studied the long-term effects of a low dose of caffeine in male 3xTg-AD mice and as compared to age-matched non-transgenic (NTg) counterparts with normal aging. Animals were treated (water or caffeine in drinking water) from adulthood (6 months of age) until middle-aged (13 months of age), that in 3xTg-AD mice correspond to onset of cognitive impairment and advanced stages, respectively. The low caffeine dosing used (0.3 mg/ml) was previously found to give a plasma concentration profile in mice roughly equivalent to that of a human coffee drinker. There were significant effects of caffeine on most behavioral variables, especially those related to neophobia and other anxiety-like behaviors, emotionality, and cognitive flexibility. The 3xTg-AD and NTg mice were differently influenced by caffeine. Overall, the increase of neophobia and other anxiety-related behaviors resulted in an exacerbation of BPSD-like profile in 3xTg-AD mice. Learning and memory, strongly influenced by anxiety in 3xTg-AD mice, got little benefit from caffeine, only shown after a detailed analysis of navigation strategies. The worsened pattern in NTg mice and the use of search strategies in 3xTg-AD mice make both groups more similar. Circadian motor activity showed genotype differences, which were found to be enhanced by caffeine. Selective effects of caffeine on NTg were found in the modulation of behaviors related to emotional profile and risk assessment. Caffeine normalized splenomegaly of 3xTg-AD mice, a physical indicator of their impaired peripheral immune system, and trended to increase their corticosterone levels. Our observations of adverse caffeine effects in an Alzheimer’s disease model together with previous clinical observations suggest that an exacerbation of BPSD-like symptoms may partly interfere with the beneficial cognitive effects of caffeine. These results are relevant when coffee-derived new potential treatments for dementia are to be devised and tested.

Impact of Social Isolation on the Behavioral, Functional Profiles, and Hippocampal Atrophy Asymmetry in Dementia in Times of Coronavirus Pandemic (COVID-19): A Translational Neuroscience Approach

“…However, differences with NTg counterparts were lost since the coping strategy exhibited was a fight-to-flight behavior that counteracted the low activity levels due to the AD-genotype. This was similar to the psychostimulant effect that our laboratory has shown in this animal model after chronic treatment with caffeine ( 68 ).…”

Vibrating Tail, Digging, Body/Face Interaction, and Lack of Barbering: Sex-Dependent Behavioral Signatures of Social Dysfunction in 3xTg-AD Mice as Compared to Mice with Normal Aging

“…feine [18]. This behavior has been considered to serve to measure digging rather than evoke burying [19], while Deacon [20] typified marble burying and digging in mice as simple methods for in vivo identification of biological impacts.…”

The Adenosinergic Signaling: A Complex but Promising Therapeutic Target for Alzheimer’s Disease

“…Thus, a growing body of evidence indicates that caffeine is able to reduce behavioral and pathological features associated with AD in models of sporadic and early onset (genetically-linked) AD. It is however important to mention that a recent study performed in transgenic mice developing both amyloid and Tau lesions suggests that chronic caffeine consumption may lead to adverse effect notably by enhancing BPSD (Behavioral and Psychological Symptoms of Dementia)-like symptoms that may interfere with the ability of caffeine to normalize memory deficits ( Baeta-Corral et al, 2018 ), underlying possible side effects that need to be carefully evaluated in future trials in patients. Overall, while a large amount of epidemiological and experimental evidence implies that caffeine and associated methylxanthines may have beneficial long-term protective effects against late-life cognitive impairment or decline, clinical evaluations are still warranted.…”