Table 3.

Effects of diet on brain plasticity in animal studies of aging and AD from 2010 onwards.

Model	Dietary factor	Intervention	Cellular and molecular mechanisms	Behavioral effects	Conclusion/proposed mechanism	Reference
F1 male Fischer 344 × Brown Norway (F344 × BN) rats	CR	Lifelong 40% CR from 4 m of age in young (10 m) versus old (29 m) rats	No effect upon spine number, density, or morphology in CA3	N/A	CR alters synaptic protein levels rather than number to compensate for synaptic loss	[212]
Male Wistar rats	CR	Lifelong CR comprising 50% of the mean daily intake of the AL group every 2nd day for middle-aged (12 m), aged (18 m), and old (24 m) rats	Counteract age-related alterations of the presynaptic proteins SPH, GAP-43, and α-syn	N/A	CR ↑synaptic remodelling and ultimately changes synaptic function and/or structure in the absence of a change in synapse number	[76]
Rat	EPA or DPA	Groups of young (3-4 m) and aged (20–22 m) rats treated with EPA and DHA for 56 d	Deficits in LTP are reversed in the aged rats that received EPA or DPA	Deficits in spatial learning are reversed in the aged rats that received EPA or DPA	Preservation of cognitive function following n-3 PUFA supplementation in aged animals is supported by complementary anti-inflammatory, antioxidative, and metabolic effects	[203]
Male Sprague-Dawley rats	CUR	Short-term (6 w) and long-term (12 w) curcumin-supplemented diet to old rats (15 m)	12 w intervention ↑neurogenesis; 12 w treatment markedly upregulated genes implicated in synaptic transmission and memory formation, for example, Cav1 gene—implicated in both cholesterol metabolism in AD and synaptic plasticity	Only 12 w treatment ↑spatial memory	Beneficial effects, explained by the enhancing of adult neurogenesis and synaptic plasticity, may require an accumulated effect of the active metabolites over a prolonged period	[147]
Transgenic mouse model of AD (Tg2576)	Grape-derived polyphenolic preparation comprising a mixture of PAC	5 m treatment starting at 7 m of age (before AD neuropathology/cognitive deficits). 10 d treatment to assess pharmacokinetics and bioavailability. Tg2576 mice aged 22–24 m used to assess the effect of PAC metabolites on LTP	↑levels of metabolites from PAC monomers were detected in the plasma and brain of mice. Biosynthetic PAC monomer metabolite ↑LTP in the CA1 region and ↑phosphorylation of CREB at [Ser133]	Only the monomeric PAC improved spatial memory retention	Brain-targeted metabolite derived from a polyphenol is capable of restoring synaptic plasticity in the AD-afflicted hippocampal formation	[159]
Male Wistar rats	IF	Old rats (at 70% of their lifespan) maintained on short-term (3 m) IF regimen	Partial restoration of expression levels of SPH and calcineurin in the CA3 and DG	Attenuation of age-associated impairments in spatial learning and motor coordination	Beneficial effect of IF regimen on learning and memory is mediated by expression of synaptic proteins regulating calcium homeostasis	[112]
Embryonic 14–16 d cortico-hippocampal neuronal cultures derived from Tg2576 AD mice	Cabernet Sauvignon (red wine derived poylphenol)	Cells were treated with varying doses of the polyphenols equivalent to moderate daily wine consumption in humans	Caberent Sauvignon brain-targeted metabolite quercetin-3-0-glucuronide reverses AD-type deficits in hippocampal basal synaptic transmission and LTP, via activation of cellular modulators of CREB protein signalling pathways.	N/A	Quercetin-3-O-glucuronide in the brain may simultaneously modulate multiple independent AD disease-modifying mechanisms, including enhancing synaptic plasticity	[160]
ApoE4-carrier and ApoE knockout mice	Multinutriet diet Fortasyn (FC), containing DHA, EPA, phospholipids, uridine monophosphate (UMP), choline, B vitamins, and antioxidants	At 2 months of age, the mice were put on either control or FC diet for the remainder of the experiment. Behavioral testing was performed at 9 m. MR imaging was performed at 11 m	No change in the levels of synaptophysin and neurogenesis MRS revealed decreased levels of glutamate in both the apoE knockout and wild-type mice increase in CBV in a region of mid-brain in the apoE ko and wild-type mice fed	Anxiolytic effect on apoE ko and wild-type mice. Improved learning and spatial memory performance only in the apoE knockout mice	n-3 PUFAs seem to exert their beneficial effects by improving synaptic function rather than by increasing synaptogenesis. Increase in CBV possibly reflects improvement in brain perfusion	[213]
Male transgenic mouse models of AD (AβPP-PS1)	Diet enriched with DHA, EPA, and UMP (DEU diet) or diet enriched with DHA, EPA, UMP as well as phospholipids, choline, folic acid, vitamins B6, B12, C, E, and selenium (FC diet)	Feeding the diets started when the mice reached the age of 2 months and was maintained for the remainder of the experiment. Animals underwent behavioral testing at 11 months of age and subsequently MRS measurements at 12 months of age	Both diets had no effect on reversing declines in the levels of N-acetylaspartylglutamate (tNAA) FC but not the DEU diet had a significantly higher amount of doublecortin positive cells FC diet ↓hippocampal levels of unbound choline-containing compounds in wild-type and transgenic animals	FC diet exerts an anxiolytic response Both DEU and FC diets had no effect on attenuating spatial learning or memory deficits	The FC diet was more effective than the DEU diet in counteracting neurodegenerative aspects of AD and enhancing processes involved in neuronal maintenance and repair. Specific multinutrient diets can influence AD pathophysiology, including enhancing brain plasticity.	[175]
20-month-old male Sprague-Dawley rats	CR	40% CR for 12 months	Prevented age-induced decrease of NPY5 receptors in CA2	N/A	Regulation of NPY receptors in the old brain by long-term CR protects neural circuits involved in cognition, emotion, and feeding functions	[83]
300–350 g male Wistar rats	CUR or CUR-LNC or Aβ + CUR or Aβ + CUR-LNC	50 mg/kg (CUR) or 2.5 mg/kg (CUR-LNC) once daily for 10 days beginning 4 days after Aβ	Prevented Aβ-induced ↓of hippocampal SPH and BDNF	Prevented Aβ-induced cognitive impairment (NORT)	Neuroprotective effects of CUR on Aβ-induced memory impairment could be linked to Akt/GSK-3β pathway activation and ↑BDNF expression	[161]
18-month-old male Wistar rats	Pure anthocyanins, pure blueberry powder, or pure flavanols	2% for 6 weeks	↑BDNF levels and ↑BDNF mRNA expression in the hippocampus (anthocyanins)	↑spatial memory in an alternation task	Flavonoids likely exert causal effects on the cognitive improvement induced by flavonoid-rich foods	[129]

Effects of different proneural plasticity dietary interventions (CR, IF, and polyphenolic/fatty acid supplementation) on brain function and behavior in recent animal studies (2010 onwards) of aging and Alzheimer's disease (AD). α-Syn: α-synuclein; BDNF: brain-derived neurotrophic factor; CBV: cerebral blood volume; CR: calorie restriction; CREB: cAMP responsive-element binding; CUR: curcumin; CUR-LNC: curcumin in lipid nanocapsule; DEU: n-3 fatty-acid enriched diet; FC: n-3 fatty-acid enriched diet supplemented with additional factors such as polyphenols; GAP-43: growth-associated protein 43; IF: intermittent fasting; LTP: long-term potentiation; NORT: novel object recognition test; NPY: neuropeptide Y; NPY-5: neuropeptide Y type 5 receptor; PAC: proanthocyanidins; p-CREB: phosphorylated CREB; SPH: synaptophysin.