Table 1 |.
Treatments that improve brain energetics and/or function in preclinical models of NDAs
| Study characteristics | Primary end points: results | Ref. |
|---|---|---|
| Mitochondrial function | ||
| AD mice (3xTg) receiving MitoQ (100 μM in drinking water) for 5 months | Mitochondrial function: ↓ cognitive decline, ↓oxidative stress, ↓ Aβ accumulation, ↓ astrogliosis, ↓ synaptic loss, ↓ caspase activation, ↓ neuropathology, ↑ mitochondrial function | 257 |
| AD mice (APP/PS1) receiving CP2 at 25 mg kg−1 per day for 14 months | Mitochondrial function:↓ complex I activity, ↑ AMPK level, ↑ mitochondrial bioenergetics | 128 |
| AD mice (APP/PS1) receiving 25–250 μM AP39 in neurons in culture; 100 nmol AP39 per kilogram body weight for 6 weeks | Brain energy status and mitochondrial function: ↑ brain ATP level, protected against mitochondrial DNA damage, ↓ ROS concentration, ↓ brain atrophy | 258 |
| AD mice (APP/PS1) receiving mdivi-1 at 10 or 40 mg kg−1 by gavage for 1 month | Mitochondrial dynamics: ↓ mitochondrial fragmentation, ↓ loss of mitochondrial membrane potential, ↓ ROS concentration, ↓ synaptic dysfunction,↑ ATP concentration, ↑ learning and memory, ↑ mitochondrial function | 136 |
| AD mice (APP/PS1) receiving nicotinamide riboside at 400 mg kg−1 per day for 10 weeks | Mitochondrial function and proteostasis: ↓ Aβ accumulation, ↑ cognitive function, ↑ oxidative phosphorylation activity | 259 |
| PD rats (hA53T-α-syn) receiving mdivi-1 at 20 mg kg−1 by intraperitoneal injection for 8 weeks | Mitochondrial dynamics: ↓ mitochondrial fragmentation, ↓ mitochondrial dysfunction, ↓ oxidative stress, ↓ neurodegeneration and α-syn aggregates, ↑ motor function | 135 |
| HD mice (HD R6/2 and YAC128) receiving DA1 peptides (1 mg kg−1 per day) via osmotic pump for 2–3 months | Mitochondrial dynamics and function: ↑ mitochondrial biogenesis and bioenergetics, ↓ inflammation and neuropathology | 260 |
| ALS mice (Sod1G93A) receiving MitoQ (500 μM in drinking water) for 30–40 days | Mitochondrial function: ↓ nitroxidative stress, ↓ neuropathology, ↑ mitochondrial function and lifespan | 261 |
| SCA1 mice (Sca1154Q/2Q) receiving MitoQ (500 μM in drinking water) for 16 weeks | Mitochondrial function: ↓ neuropathology, ↓ oxidative stress, ↓ DNA damage, ↓ neuronal loss, ↑ mitochondrial function | 262 |
| Seizure model (risk of AD). In vivo study: CD1 mice; 35% of energy from C10 in regular diet. In vitro study: astrocytes exposed to 200 mM C8 or C10 for 10 days | Seizures — in vivo study: ↓ seizures after C10 but not C8; no change in levels of glycolytic enzymes. In vitro study: C8 and C10: ↑ basal respiration and mitochondrial leak; ↑ ATP synthesis, ↑ antioxidant capacity caused by C10 but not C8 | 150 |
| Insulin sensitizers | ||
| AD mice (APP/PS1) receiving metformin at 200 mg kg−1 intraperitoneally for 14 days | Cognitive performance, neuropathology: ↑ cognitive performance (Morris water maze), ↓ hippocampal neuron loss, ↓ Aβ accumulation, ↓ neuroinflammation | 176 |
| HD mice (Hdh150 knock-in) receiving metformin in drinking water at 5 mg ml−1 for 3 weeks | Early network hyperactivation in visual cortex, behaviour: ↓ hyperactive neurons, ↑ normal network patterns, ↓ green fluorescent protein–huntingtin synthesis, ↓ anxiolytic behaviour | 177 |
| Ketogenic molecules | ||
| AD mice (APP/PS1) receiving BHB and pyruvate at 26 mg kg−1 per day for 5 weeks | Brain redox status: ↑ brain nicotinamide adenine dinucleotide phosphate (reduced) level; ↓ network hyperactivity (epileptiform discharges) | 146 |
| AD mice (3xTgAD) receiving 125 g ketone ester per kg in diet for 8 months | Brain TCA cycle activity, mitochondrial function: BHB level ↑ fivefold; 30–40% ↑ in level of brain TCA cycle and glycolytic intermediates; ↑ mitochondrial redox potential; ↓ level of oxidized lipids/proteins in hippocampus | 263 |
| AD mice (Sirt3+/−/AppPs1) receiving ketone ester added at 22% of dietary energy for 20 weeks | Neurodegeneration, neuronal network hyperexcitability: ↑ cortical SIRT3 expression, ↓ loss of GABAergic neurons, ↓ seizures and prevented death of Sirt3+/−/AppPs1 mice | 264 |
| PD mice receiving MPTP at 18 mg kg−1 4 times over 2 h and BHB at 40, 80 or 160 mg kg−1 per day for 7 days | Mitochondrial function: ↑ mitochondrial respiration and ATP at complex II, ↓ dopamine neurodegeneration and motor deficit | 265 |
| ALS mice (SOD1-G93A) receiving 10% of calories as C8 for 10 weeks (7–17 weeks old) | Physical symptoms: ↑ mitochondrial function, ↓ spinal cord motor neuron loss, ↑ mitochondrial O2 consumption, no change in survival | 266 |
| Nutrients and metabolites | ||
| AD mice (Tg2576) receiving nicotinamide riboside at 250 mg kg−1 per day for 3 months | Brain redox status, cognitive performance: ↑ cortical redox status; attenuated cognitive decline | 267 |
| AD mice (3xTgAD/Polb+/−) receiving nicotinamide riboside at 3 g l−1 (12 mM) in drinking water for 6 months | Brain redox status: normalized cortical NAD+/NADH; nicotinamide riboside ↑ cognitive function and restored hippocampal synaptic plasticity | 142 |
| AD mice (treated with streptozotocin) receiving N-acetylcysteine at 50 mg kg−1 for 9 days | Brain glucose uptake, cognitive performance: normalized glucose uptake in hippocampus after streptozotocin treatment; prevented spatial/non-spatial learning and memory impairment | 268 |
| ALS mice (SOD1G93A) receiving 35% of calories as triheptanoin for 5 weeks (35–70 days old) | Physical performance, TCA cycle activity, brain glucose uptake, cognitive performance: ↑ hindlimb grip strength by 2.8 weeks, ↑ time to loss of balance on rotarod, ↑ time before weight loss, ↑ TCA cycle | 269 |
Reports shown here exclude those involving the ketogenic diet and lifestyle interventions (see BOX 3); studies involving antioxidants are documented in other reviews60. Triheptanoin269 is a seven-carbon triglyceride. The APP/PS1 Alzheimer disease (AD) mice bear the APP Swedish mutation plus the PS1-L166P mutation. 3xTgAD mice express three mutant proteins (APP Swedish, PS1-M146L and tau-P301L). ↑, increase; ↓, decrease; 3xTg, triple transgenic (amyloid precursor protein, tau and presenilin-1); Aβ, amyloid-β; AMPK, AMP-activated protein kinase; ALS, amyotrophic lateral sclerosis; AP39, proprietary mitochondrial-targeted H2S donor; BHB, d-β-hydroxybutyrate; C8, octanoic acid; C10, decanonic acid; DA1, dynamin-related protein antagonist 1; hA53T, adenosine to threonine missense mutation at position 53 of human synuclein; HD, Huntington disease; mdivi-1, mitochondrial division inhibitor 1; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NDAs, neurodegenerative disorders of ageing; PD, Parkinson disease; Pol, DNA polymerase; ROS, reactive oxygen species; SCA1, spinocerebellar ataxia type 1; α-Syn, α-synuclein; TCA, tricarboxylic acid; YAC, yeast artificial chromosome.