Every-Other-Day Feeding Prevents the Loss of Parvalbumin-Expressing Neurons in the Cerebral Cortex of Female 5xFAD Mice

The present study demonstrates the effects of an every-other-day (EOD) feeding regimen on parvalbumin (PV)-expressing interneurons in the cortex of 5xFAD mice, a well-established animal model of Alzheimer's disease (AD). Female 5xFAD mice and their non-transgenic littermates were maintained on either an ad libitum (AL) or EOD feeding regimen throughout the presymptomatic phase of the pathology, with comprehensive immunohistochemical and Western blot analyses performed in 6-month-old animals. In AL-fed 5xFAD mice, significant reductions in PV-expressing interneurons were observed in the retrosplenial granular, parietal, and somatosensory cortices compared to non-transgenic controls, supporting their established vulnerability in AD pathology. This neuronal loss was accompanied by a decline in the levels of brain-derived neurotrophic factor (BDNF), a key neurotrophin essential for cell survival and synaptic plasticity. Remarkably, four months of EOD feeding prevented the Aβ-induced loss of PV interneurons and increased the total protein levels of the BDNF receptor TrkB, suggesting enhanced neurotrophic signaling. However, the benefits of EOD feeding were not uniform across all molecular markers, with EOD-fed 5xFAD mice retaining deficits in phosphorylated CaMKII and CREB-binding protein (CBP) and biochemical analysis of plasma indicating metabolic stress-related effects. Together, these results align with the GABAergic hypofunction hypothesis in AD, underscoring the importance of PV interneuron plasticity in neurodegeneration and cognitive decline. They also suggest that dietary strategies like EOD feeding may offer partial neuroprotective effects during early AD progression, however, complex stress-related impacts of EOD in the modulation of PV neuron function remain to be elucidated. Future studies are also warranted to more carefully explore the long-term translational potential of dietary interventions and the interplay between metabolic stress and amyloid pathology, in order to identify novel therapeutic targets across distinct neuronal populations.