Table 1.
Cyanobacteria-derived products/extracts studied in AD disease models.
| Strain | Compound/Extract | Effect | In Vitro Assays | In Vivo Assays | Reference |
|---|---|---|---|---|---|
|
Anabaena flos-aquae NRC-525-17 |
Anatoxin-a(s) (3) | AChE and BChE inhibition | AChE and BChE inhibition assay | [55] | |
| Nostoc 78-12A | Nostocarboline (4) | BChE inhibition | AChE and BChE inhibition assay | [57] | |
| Phormidium autumnale | SFE-EtOH extract | AChE and LOX inhibition. Antioxidant. |
AChE inhibition assay. LOX inhibition assay. ORAC assay. |
[60] | |
| Anabaena variabilis | Methylene chloride/ methanol extract (Fraction 7) |
AChE inhibition | AChE inhibition assay | [61] | |
| Oscillatoria sancta | Methylene chloride/ methanol (1:1) extract |
AChE inhibition | AChE inhibition assay | [62] | |
| Nostoc sp. | Ethanolic Extract | AChE and BChE inhibition. Antioxidant. |
AChE and BChE inhibition assay. DPPH assay. |
[63] | |
| Spirulina sp. | Phycocyanin | Inhibition of Aβ formation |
Fluorimetric assay. Kinetic analysis. Circular dichroism analysis. |
[65] | |
| Spirulina sp. | Phycocyanin | Inhibition of Aβ40/42 amyloid fibrillation |
Fibrillar and amorphous aggregation assays. Transmission electron microscopy imaging. |
[66] | |
| Symploca sp. | Tasiamide B (8) | BACE-1 inhibition | BACE-1 inhibition assay | [67] | |
| Lyngbya sp. | Tasiamide F (9) | BACE-1 inhibition | BACE-1 inhibition assay | [69] | |
|
Leptolyngbya sp. N62DM |
Phycocyanin | BACE-1 inhibition | Protein-complex interface identification |
Caenorhabditis elegans CL4176 transgenic AD-model: Paralysis assay |
[70] |
|
Lyngbya sp. A09DM |
Phycoerythrin | BACE-1 inhibition | Surface plasmon resonance. Isothermal titration calorimetry. Enzyme activity by kinetic parameters. |
Caenorhabditis elegans CL4176 transgenic AD-model: Thioflavin-T staining assay |
[71] |
| Spirulina platensis | Lipopolysaccharide | Downregulation of p-tau expression. Antioxidant. Anti-inflammatory. |
Wistar albino rats exposed to nicotine: Biochemical assessments (Oxidative and inflammatory markers). RT-PCR. Western Blot (p-tau). |
[78] | |
| Spirulina maxima | 70% ethanol extract | AChE inhibition. Reduced Aβ, APP, and BACE-1 levels. BDNF/PI3K/Akt pathway activation. Antioxidant. Improved cognition. |
ICR mice injected with Aβ1–42: Passive Avoidance Test. Morris WaterMaze Test. Biochemical Analysis (Aβ1–42, GSH, BDNF, AChE). Western Blot. |
[72] | |
| Aphanizomenon flos-aquae | KlamExtra® | Reduced Aβ, APP and BACE-1 levels. Anti-inflammatory and anti-gliosis. Improved metabolic parameters. Protection of neuronal morphology and synapses. |
High-Fat Diet C57BL/6J mice: Metabolic parameters analysis. Western Blot (IR, Akt, PSEN-1, BACE-1, PSD-95, synaptophysin, TNF-α, GFAP, IL-10, TREM-2). Histopathology and Immunohistochemistry (GFAP, TREM-2, Aβ). Thioflavin T staining. TUNEL assay. |
[73] | |
| Spirulina platensis | Diet supplementation | Decreased Aβ1–42, APP, BACE-1, p-tau, and p-GSK levels. Anti-inflammatory. Improved microbiota dysbiosis. Improved metabolic parameters. Improved locomotor and cognitive function. | High-Fat Diet C57BL/6J mice: Barnes Maze test. Morris Water Maze test. ELISA (Aβ1–42, TNF-α, IL-1β, IL-6, LPS). RT-PCR. Western Blot (APP, BACE-1, p-tau, p-GSK, IBA-1). Microbial diversity analysis. GC (SCFAs). |
[79] | |
| cf. Symploca sp. | Santacruzamate A (11) | Anti-apoptotic. Anti-UPR and ER stress. Improvement of the mitochondrial fission pathway. Modulation of KDELR and Mia40-ALR. Memory improvement. |
PC12 cells: Cell viability and apoptosis assays. Electrophysiological recordings. Immunoblot analyses. Measurement of mitochondrial permeability transition pore. Opening and mitochondrial membrane potentials. |
APPswe/PS1dE9 mice: Open-Field test. Morris Water Maze test. RT-PCR (Mia40, KDEL). |
[80] |
| Spirulina platensis | Diet supplementation (tablets) |
Protection of neuronal morphology. Reduction in Aβ accumulation. Improvement of metabolic parameters. Antioxidant. Anti-inflammatory. |
Wistar rats treated with AlCl3: TBARS assay. GSH content assay. Total thiol content assay. TAC assay. GPx, GST, SOD activity assay. Lipid profile determination. ELISA (TNF-α). Histology. Immunofluorescence (Aβ). |
[82] | |
| Spirulina platensis |
S. platensis- loaded niosome |
Protection of neuronal morphology. Restored levels of AChE and ACh. Gene modulation. Recognition and working memory improvement. |
Wistar rats treated with AlCl3: Novel object recognition test. Y-maze test. TAC assay. MDA assay. AChE assay. Histology. HPLC (ACh, NE, 5HT, DA, DOPAC). qPCR (Bax, Bcl-2, AChE, MAO). |
[83] | |
| Spirulina platensis | Enzyme Digested Phycocyanin (EDPC) |
Cognitive function improvement. Gene modulation. |
Male Slc:ddY SPF mice injected with Aβ25–35: Y Maze test. DNA microarray. |
[85] | |
| Spirulina platensis | Phycocyanin | Gene and miRNA modulation. Anti-inflammatory. Anti-apoptotic. Memory improvement. | Male C57BL/6 mice injected with oligomeric Aβ1–42: Eight-arm radial maze. RT-PCR (caspase-3, caspase-9, miR-335). Western Blot (HDAC3, Bcl-2, Bax, IL-6, IL-1β). Immunohistochemistry (Bcl-2, Bax). Immunofluorescence (BDNF, HDAC3). |
[86] | |
| Spirulina platensis | Phycocyanin | AChE inhibition. ChAT activity increase. Gene modulation. Increased PI3K/Akt pathway. Anti-inflammatory. Memory improvement. |
Female Wistar Rats injected with STZ: Morris Water Maze. Memory consolidation test. Novel object recognition test. Open field test. AChE and ChAT activity assays. ELISA (TNF-α, NF-kB p56, Bcl-2, Bax, BDNF, IGF-1). qRT-PCR (IRS-1, INS, PI3K, Akt, PTEN). |
[87] | |
| Spirulina maxima | 70% ethanolic extract (SM70EE) pills |
Memory and vocabulary improvement. |
Randomized, double-blind, and placebo- controlled clinical trial. Visual learning, visual working memory, and verbal learning tests. |
[88] | |
| Spirulina platensis | Dietary supplementation | Improved cognitive function. Improved metabolic status. |
Randomized, double-blind, and placebo. -controlled clinical trial. Mini-mental state exam. ELISA (hs-CRP, Insulin). Biochemical analysis (NO, TAC, GSH, MDA, FPG, lipid profile). |
[89] |
Abbreviations: AChE—Acetylcholinesterase. BChE—Butyrylcholinesterase. SFE-EtOH—Supercritical Fluid Extraction with Ethanol. LOX—Lipoxygenase. ORAC—Oxygen Radical Absorbance Capacity. DPPH—2,2-diphenyl-1-picrylhydrazyl. BACE-1—Beta Secretase 1. AD—Alzheimer’s Disease. Aβ—Beta-amyloid peptide. APP—Amyloid-beta Precursor Protein. BDNF—Brain-derived Neurotrophic Factor. PI3K—Phosphoinositide 3-kinase. Akt—Protein kinase B. TBARS—Thiobarbituric Acid Reactive Substances. GSH—Total Glutathione. IR—Insulin receptor. PSEN-1—Presenilin-1. PSD-95—Postsynaptic density protein 95. TNF-α—Tumor Necrosis Factor α. GFAP—Glial fibrillary acidic protein. IL-10—Interleukin. TREM-2—Triggering receptors expressed on myeloid cells-2. p-tau—Phosphorylated Tau. p-GSK—Phosphorylated Glycogen Synthase. LPS—Lipopolysaccharide. RT-PCR—Reverse Transcription Polymerase Chain Reaction. Iba-1—Ionized calcium-binding adaptor molecule 1. GC—Gas Chromatography. SCFAs—Short-chain fatty acids. UPR—Unfolded Protein Response. ER—Endoplasmic Reticulum. KDELR—Endoplasmic Reticulum Protein Retention Receptor. Mia40—Mitochondrial Intermembrane Space Assembly Protein 40. ALR—Augmenter of the Liver Regeneration. AlCl3—Aluminum Chloride. TAC—Total Antioxidant Capacity. GPx—Glutathione Peroxidase. GST—Glutathione S-transferase. SOD—Superoxide Dismutase. ELISA—Enzyme-Linked Immunosorbent Assay. MDA—Malondialdehyde. HPLC—High-Performance Liquid Chromatography. ACh—Acetylcholine. NE—Norepinephrine. 5HT—Serotonin. DA—Dopamine. DOPAC—3,4-Dihydroxyphenylacetic acid. Bcl-2—B-cell Lymphoma-2. Bax—Bcl-2 Associated X-protein. MAO—Monoamine oxidase. HDAC3—Histone deacetylase 3. STZ—Streptozotocin. ChAT—Choline acetyltransferase. NF-kβ—Nuclear Factor Kappa β. IGF-1- Insulin-like growth factor 1. IRS-1—Insulin receptor substrate 1. INS—Insulin Gene. PTEN—Phosphatase and Tensin Homolog. hs-CRP—High sensitivity C-reactive protein. NO—Nitric Oxide. FPG—Fasting Plasma Glucose. Human clinical trials have also validated the potential of Spirulina as a nutraceutical. Patients with mild cognitive impairment who consumed 1 g/day of S. maxima 70% ethanol extract (SM70EE) capsules experienced statistically significant gains in visual learning and working memory according to a randomized, double-blind, and placebo-controlled clinical trial [88]. Another randomized, double-blind, and controlled clinical trial investigated the cognitive and metabolic status of patients with AD who took S. platensis capsules twice daily (500 mg/day). Supplementation considerably improved the Mini-Mental State Examination score, indicating an enhancement in cognitive function. It also had a favorable impact on the metabolic status by lowering C-reactive protein, fasting glucose, insulin levels, and insulin resistance while increasing insulin sensitivity [89].