No abstract

Tau hyperphosphorylation at several sites, including those close to the microtubule domain region (MDr), is considered a key pathological event in the development of Alzheimer's disease (AD). Recent studies indicate that at the very early stage of this disease, increased phosphorylation in Tau's MDr domain correlates with reduced levels of neuronal excitability. Mechanistically, we show that pyramidal neurons and some parvalbumin-positive interneurons in 1-month-old triple-transgenic AD mice accumulate hyperphosphorylated Tau protein and that this accumulation correlates with changes in theta oscillations in hippocampal neurons. Pyramidal neurons from young triple-transgenic AD mice exhibited less spike accommodation and power increase in subthreshold membrane oscillations. Furthermore, triple-transgenic AD mice challenged with the potassium channel blocker 4-aminopyridine had reduced theta amplitude compared with 4-aminopyridine-treated control mice and, unlike these controls, displayed no seizure-like activity after this challenge. Collectively, our results provide new insights into AD pathogenesis and suggest that increases in Tau phosphorylation at the initial stages of the disease represent neuronal responses that compensate for brain circuit overexcitation.

Neural plasticity is an intrinsic and essential characteristic of the nervous system that allows animals “self-tuning” to adapt to their environment over their lifetime. Activity-dependent synaptic plasticity in the central nervous system is a form of neural plasticity that underlies learning and memory formation, as well as long-lasting, environmentally-induced maladaptive behaviors, such as drug addiction and overeating of palatable hyper-caloric (PHc) food. In western societies, the abundance of PHc foods has caused a dramatic increase in the incidence of overweight/obesity and related disorders. To this regard, it has been suggested that increased adiposity may be caused at least in part by behavioral changes in the affected individuals that are induced by the chronic consumption of PHc foods; some authors have even drawn attention to the similarity that exists between over-indulgent eating and drug addiction. Long-term misuse of certain dietary components has also been linked to chronic neuroimmune maladaptation that may predispose individuals to neurodegenerative conditions such as Alzheimer’s disease. In this review article, we discuss recent evidence that shows how consumption of PHc food can cause maladaptive neural plasticity that converts short-term ingestive drives into compulsive behaviors. We also discuss the neural mechanisms of how chronic consumption of PHc foods may alter brain function and lead to cognitive impairments, focusing on prenatal, childhood and adolescence as vulnerable neurodevelopmental stages to dietary environmental insults. Finally, we outline a societal agenda for harnessing permissive obesogenic environments.

The effect of prenatal protein deprivation on the postnatal development of granule cells in the fascia dentata in the rat was studied at 15, 30, 90, and 220 days of age. The granule cells showed a significant reduction in cell size, decreased number of synaptic spines throughout their dendritic extent, and reduced complexity of dendritic branching in the outer two-thirds of the molecular layer. All of these deficits were present at 15 days and persisted throughout the study (220 days). The least deficits in synaptic spine density occurred at 90 days and in dendritic branching at 30 days. Partial restitution of earlier, more severe deficits was associated primarily with maturational events occurring in the protein deprived rats, whereas later increases in deficits were related primarily to a failure of the protein deprived rats to keep pace with neuronal development occurring in the controls. The present results are similar to those noted in our previous study in this journal of the effect of a low protein diet (8% casein) on these neurons that extended from pregnancy until the time of sacrifice at 30, 90, and 220 days of age (Cintra et al., '90; 532:271-277). Taken together, these two studies suggest that the postnatal adaptation of the granule cells to prenatal protein deprivation is primarily due to events that occur during pregnancy and that the site of predilection for the deficit is their dendrites in the outer two-thirds of the molecular layer of the fascia dentata.