Ketones block amyloid entry and improve cognition in an Alzheimer's model.

Sporadic Alzheimer's disease (AD) is responsible for 60%-80% of dementia cases, and the most opportune time for preventive intervention is in the earliest stage of its preclinical phase. As traditional mitochondrial energy substrates, ketone bodies (ketones, for short), beta-hydroxybutyrate, and acetoacetate, have been reported to provide symptomatic improvement and disease-modifying activity in epilepsy and neurodegenerative disorders. Recently, ketones are thought as more than just metabolites and also as endogenous factors protecting against AD.

Pituitary adenylate cyclase-activating polypeptide protects against β-amyloid toxicity.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neurotrophin. However, its role in human Alzheimer's disease (AD) is largely unknown. We examined PACAP expression in postmortem human AD and triple transgenic mouse (3xTG, Psen1/APPSwe/TauP301L) brains.

Association of amyloid burden, brain atrophy and memory deficits in aged apolipoprotein ε4 mice.

Apolipoprotein E ε4 allele (ApoE4) has been associated with increased risk of sporadic Alzheimer's disease (AD) and of conversion from mild cognitive impairment to AD. But the underlying mechanism of ApoE4 affecting brain atrophy and cognition is not fully understood. We investigated the effect of ApoE4 on amyloid beta (Aβ) protein burden and its correlation with the structure change of hippocampus and cortex, cognitive and behavioral changes in ApoE4 transgenic mice.

Pertussis toxin attenuates experimental autoimmune encephalomyelitis by upregulating neuronal vascular endothelial growth factor.

We have reported earlier that pertussis toxin (PTx) attenuates the motor deficits in experimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis. PTx protects neurons from inflammatory insults. Vascular endothelial growth factor (VEGF) is also neuroprotective.

Acute exposure to the mitochondrial complex I toxin rotenone impairs synaptic long-term potentiation in rat hippocampal slices.

Aims: To evaluate the acute effects of the mitochondrial complex I inhibitor rotenone on rat hippocampal synaptic plasticity.

Methods: Electrophysiological field potential recordings were used to measure basal synaptic transmission and synaptic plasticity in rat coronal hippocampal slices. Synaptic long-term potentiation (LTP) was induced by high-frequency stimulation (100 Hz, 1 second × 3 at an interval of 20 seconds).

An update on the diagnosis and management of dementing conditions.

Worsening memory is a common complaint in the elderly and predictably causes affected individuals and their families to wonder whether the underlying cause is Alzheimer disease, the most common form of dementia. Alzheimer disease is a devastating illness that unavoidably leads to a complete loss of independence and, as a result, substantial emotional, physical, and financial distress for patients and their families. The causes and severity of memory impairment in the elderly are diverse, however, so any given case might not necessarily be secondary to a neurodegenerative disorder such as Alzheimer disease.

Dissociated fear and spatial learning in mice with deficiency of ataxin-2.

Mouse models with physiological and behavioral differences attributable to differential plasticity of hippocampal and amygdalar neuronal networks are rare. We previously generated ataxin-2 (Atxn2) knockout mice and demonstrated that these animals lacked obvious anatomical abnormalities of the CNS, but showed marked obesity and reduced fertility. We now report on behavioral changes as a consequence of Atxn2-deficiency.

The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies.

Both calorie restriction and the ketogenic diet possess broad therapeutic potential in various clinical settings and in various animal models of neurological disease. Following calorie restriction or consumption of a ketogenic diet, there is notable improvement in mitochondrial function, a decrease in the expression of apoptotic and inflammatory mediators and an increase in the activity of neurotrophic factors. However, despite these intriguing observations, it is not yet clear which of these mechanisms account for the observed neuroprotective effects.

Oxidative impairment of hippocampal long-term potentiation involves activation of protein phosphatase 2A and is prevented by ketone bodies.

Previous studies have shown that ketone bodies (KB) exert antioxidant effects in experimental models of neurological disease. In the present study, we explored the effects of the KB acetoacetate (ACA) and beta-hydroxybutyrate (BHB) on impairment of hippocampal long-term potentiation (LTP) in rats by hydrogen peroxide (H(2)O(2)) using electrophysiological, fluorescence imaging, and enzyme assay techniques. We found that: 1) a combination of ACA and BHB (1 mM each) prevented impairment of LTP by H(2)O(2) (200 microM); 2) KB significantly lowered intracellular levels of reactive oxygen species (ROS)--measured with the fluorescent indicator carboxy-H(2)DCFDA (carboxy-2',7'-dichlorodihydrofluorescein diacetate)--in CA1 pyramidal neurons exposed to H(2)O(2); 3) the effect of KB on LTP was replicated by the protein phosphatase 2A (PP2A) inhibitor fostriecin; 4) KB prevented impairment of LTP by the PP2A activator C(6) ceramide; 5) fostriecin did not prevent the increase in ROS levels in CA1 pyramidal neurons exposed to H(2)O(2), and C(6) ceramide did not increase ROS levels; 6) PP2A activity was enhanced by both H(2)O(2) and rotenone (a mitochondrial complex I inhibitor that increases endogenous superoxide production); and 7) KB inhibited PP2A activity in protein extracts from brain tissue treated with either H(2)O(2) or ceramide.

Ketone bodies are protective against oxidative stress in neocortical neurons.

Ketone bodies (KB) have been shown to prevent neurodegeneration in models of Parkinson's and Alzheimer's diseases, but the mechanisms underlying these effects remain unclear. One possibility is that KB may exert antioxidant activity. In the current study, we explored the effects of KB on rat neocortical neurons exposed to hydrogen peroxide (H(2)O(2)) or diamide - a thiol oxidant and activator of mitochondrial permeability transition (mPT).

Impaired motor control in patients with benign focal epilepsy of childhood.

Upper extremity motor function was quantitatively assessed in 6 children (age 7-11 years) treated with antiepileptic drugs for benign focal epilepsies of childhood and compared with that of 30 age-matched normal children. Both motor performance and adaptation to perturbing mechanical constraints imposed by a robotic device were significantly impaired in children with benign focal epilepsies of childhood. Our findings thus question whether certain "benign" epilepsies are truly benign and whether pharmacologic treatment might contribute to motor impairment.