Long-term caffeine treatment of Alzheimer mouse models ameliorates behavioural deficits and neuron loss and promotes cellular and molecular markers of neurogenesis

Abstract

Epidemiological studies indicate that the consumption of caffeine, the most commonly ingested psychoactive substance found in coffee, tea or soft drinks, reduces the risk of developing Alzheimer’s disease (AD). Previous treatment studies with transgenic AD mouse models reported a reduced amyloid plaque load and an amelioration of behavioral deficits. It has been further shown that moderate doses of caffeine have the potential to attenuate the health burden in preclinical mouse models of a variety of brain disorders (reviewed in Cunha in J Neurochem 139:1019–1055, 2016). In the current study, we assessed whether long-term caffeine consumption affected hippocampal neuron loss and associated behavioral deficits in the Tg4-42 mouse model of AD. Treatment over a 4-month period reduced hippocampal neuron loss, rescued learning and memory deficits, and ameliorated impaired neurogenesis. Neuron-specific RNA sequencing analysis in the hippocampus revealed an altered expression profile distinguished by the up-regulation of genes linked to synaptic function and processes, and to neural progenitor proliferation. Treatment of 5xFAD mice, which develop prominent amyloid pathology, with the same paradigm also rescued behavioral deficits but did not affect extracellular amyloid-β (Aβ) levels or amyloid precursor protein (APP) processing. These findings challenge previous assumptions that caffeine is anti-amyloidogenic and indicate that the promotion of neurogenesis might play a role in its beneficial effects.

Caffeine Restores Neuronal Damage and Inflammatory Response in a Model of Intraventricular Hemorrhage of the Preterm Newborn

“…Likewise, neuron population assessed by the NeuN/DAPI ratio was reduced after GM-IVH in the cortex and the SVZ from mice with GM-IVH, and Caf treatment counterbalanced this situation. These data support the capacity of Caf to limit neuronal loss, in line with previous studies showing that Caf may promote neuron survival after an hypoxic situation (Li et al, 2019;Soontarapornchai et al, 2021) or other insults (Stazi et al, 2021;Xie et al, 2021).…”

“…Interestingly, Caf treatment at the highest dose (20 mg/kg/day) successfully restored neurogenesis impairment, suggesting that Caf effects might not be circumscribed to limiting neuronal loss, but it may also promote neurogenesis. Whereas some studies have shown that Caf may compromise proliferation of human hippocampal progenitor cells (Houghton et al, 2020), neurogenesis seems to improve after Caf treatment in different animal models (Mao et al, 2020;Stazi et al, 2021).…”

Combined long-term enriched environment and caffeine supplementation improve memory function in C57Bl6 mice

“…Mice were housed in groups of 4–5 in all conditions to ensure social interactions; food and water were provided ad libitum . Data from vehicle- and caffeine-treated SH groups have been partially published in a previous study [ 63 ], where they served as control groups within a larger set of experiments to minimize experimental animal numbers. All animals were handled according to the German guidelines for animal care and all experiments have been approved by the local animal care and use committee (Landesamt für Verbraucherschutz und Lebensmittelsicherheit (LAVES), Lower Saxony, Approval number 17/2701).…”

The Role of the Adenosine System on Emotional and Cognitive Disturbances Induced by Ethanol Binge Drinking in the Immature Brain and the Beneficial Effects of Caffeine

“…There is substantial evidence that the regular consumption of moderate caffeine attenuates memory deficits [169]. This is most evident when considering the beneficial effects of caffeine intake in different models of Alzheimer's disease such as in transgenic models leading to the over-function of the amyloid cascade [170,171] or tau [172], as well as in models of sporadic Alzheimer's disease [161]. This prevention of memory deficits by caffeine is mimicked by the pharmacological or genetic blockade of A2AR [133,135,[172][173][174].…”