Table 3: Effects of diet on brain plasticity in animal studies of aging and AD from 2010 onwards.

InterventionCellular and molecular
Conclusion/proposed mechanismReference

F1 male Fischer
344 × Brown Norway
(F344 × BN) rats
CRLifelong 40% CR from 4 m of age in young (10 m) versus old (29 m) ratsNo effect upon spine number, density, or morphology in CA3N/ACR alters synaptic protein levels rather than number to compensate for synaptic loss[212]

Male Wistar ratsCRLifelong 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) ratsCounteract age-related alterations of the presynaptic proteins SPH, GAP-43, and -synN/ACR ↑synaptic remodelling and ultimately changes synaptic function and/or structure in the absence of a change in synapse number[76]

RatEPA or DPAGroups of young (3-4 m) and aged (20–22 m) rats treated with EPA and DHA for 56 dDeficits in LTP are reversed in the aged rats that received EPA or DPADeficits in spatial learning are reversed in the aged rats that received EPA or DPAPreservation 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
CURShort-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 memoryBeneficial 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 PAC5 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 retentionBrain-targeted metabolite derived from a polyphenol is capable of restoring synaptic plasticity in the AD-afflicted hippocampal formation[159]

Male Wistar ratsIFOld rats (at 70% of their lifespan) maintained on short-term (3 m) IF regimenPartial restoration of expression levels of SPH and calcineurin in the CA3 and DGAttenuation of age-associated impairments in spatial learning and motor coordinationBeneficial 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 miceCabernet Sauvignon
(red wine derived poylphenol)
Cells were treated with varying doses of the polyphenols equivalent to moderate daily wine consumption in humansCaberent 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/AQuercetin-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 miceMultinutriet diet Fortasyn (FC), containing DHA, EPA, phospholipids, uridine monophosphate (UMP), choline, B vitamins, and antioxidantsAt 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

Male transgenic mouse models of AD (A PP-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 ratsCR40% CR for 12 monthsPrevented age-induced decrease of NPY5 receptors in CA2N/ARegulation 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
or A + CUR
or A + CUR-LNC
50 mg/kg (CUR) or 2.5 mg/kg (CUR-LNC) once daily for 10 days beginning 4 days after A Prevented A -induced ↓of hippocampal SPH and BDNFPrevented A -induced cognitive impairment (NORT)Neuroprotective effects of CUR on A -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 flavanols2% for 6 weeks↑BDNF levels and ↑BDNF mRNA expression in the hippocampus (anthocyanins)↑spatial memory in an alternation taskFlavonoids 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). -Syn: -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.