Therapeutic targets and delivery challenges for Alzheimer’s disease

Table 1 Novel therapeutic strategies for Alzheimer's disease management

Active	Mechanism of action	Drug delivery system	Efficacy study model	Ref.
Oral
Rutin	Antioxidant	Only drug	Preclinical rodent streptozotocin induced AD model	[85]
(-)-Epigallocatechin-3-gallate	Antioxidant, α-secretase activator	Nanolipid carriers	In vitro, preclinical rodent model	[137]
		Chitosan	Preclinical rodent model	[138]
Mifepristone	Antiprogesterone activity, AD symptomatic relief	PLGA nanoparticles	Preclinical rodent model	[139-141]
Estradiol	Estrogenic activity, AD symptomatic relief	Tween 80 coated PLGA nanoparticles	Preclinical rodent model	[142,143]
CNTF P021 (Ac-DGGLAG-NH2)	Neurotrophic factor	Only drug	Preclinical rodent AD transgenic model	[144]
Clioquinol	Metal ion Cu/Zn chelator	Only drug	Preclinical rodent AD transgenic model	[145,146]
Galactose	Glucose restoration	Only drug	Preclinical streptozotocin induced rodent model	[147]
Transdermal
Galantamine	AChEI	Drug in adhesive type patch	Preclinical rodent model	[151]
Donepezil (base and salt form)	AChEI	Fatty acid based topical formulation	In vitro skin model, preclinical rodent model	[152]
Huperzine A	AChEI	Microemulsion, solid lipid nanoparticles, nanostructured lipid carriers	In vitro skin model, preclinical rodent model	[153]
Donepezil	AChEI	Iontophoresis, Wearable Electronic Drug Delivery System patches	Preclinical rodent model	[154]
Rasageline and selegiline	MAO-B inhibitors	Solution and carbopol based gel - iontophoresis	In vitro skin model	[155]
Memantine	NMDA receptor modulator	Iontophoresis with penetration enhancers	In vitro skin model	[156]
Aβ(1-42) antigen	AD immunovaccine	Microneedles	Preclinical rodent model	[161]
Intravenous
Clioquinol	Cu/Zn chelator	Only drug	Preclinical rodent AD transgenic model	[42]
Lithium	GSK-3 inhibitor of tau phosphorylation	Only drug	Preclinical rodent AD transgenic model	[76,77]
Valproate sodium	GSK-3 inhibitor of tau phosphorylation	Only drug	Preclinical rodent AD transgenic model	[76,77]
Nerve growth factor	Cholinergic neuron protection	Polysorbate 80 coated PBCA nanoparticles	Preclinical scopolamine induced rodent model	[162]
		PEG chemical conjugate	Preclinical rodent model	[163]
		Antitransferrin antibody chemical conjugate	Preclinical rodent model	[163,164]
Galantamine	AChEI	Peptide targeting ligand functionalized liposomes	In vitro cell line	[165]
Aβ binding peptide QSH	Aβ reduction	Targeted PEGylated polylactic acid nanocarriers	Preclinical AD induced rodent model	[166]
Thiflavin T	Specific Aβ plaque binding	PBCA Nanoparticles	Preclinical rodent model	[168,169]
Anti- Aβ antibody	AD immunotherapy	Only drug	Preclinical rodent AD transgenic model	[49,50]
BAM -10 antibody	AD immunotherapy	External targeting with trans-cranial application of magnetic and ultrasound energy	Preclinical rodent AD transgenic model	[186,187]
Cholic acid	Cholinergic management	Fluorescent labeled PEG-PLGA nanoparticles, external ultrasound	Preclinical rodent model	[188]
Octapeptide NAP derived from the neurotrophic factor	Neuroprotective activity	Only drug	Preclinical rodent model	[196,197]
Mesenchymal stem Cells	Neuronal growth	Only drug	In vitro, Preclinical transgenic AD rodent model	[203,204]
Intranasal
Insulin	Multicascade anti AD activity	Only drug	Preclinical rodent model	[130-132]
Tacrine	AChEI	Cyclodextrin coated bovine serum albumin nanospeheres	Ex vivo permeation model	[175]
Curcumin	Antioxidant, anti- Aβ activity	Nanoemulsion	Ex vivo permeation model	[177]
siRNA	AD associated gene silencing	Cell penetrating peptide TAT conjugated polycaprolactone- PEG Micelles	Early development	[184]
Gene delivery	AD associated gene silencing	Exosomes	Early development	[185]
Pituitary adenylate cyclase-activating polypeptide	Neuroprotective activity	Only drug	Preclinical rodent model	[198]
Implants
Rivastigmine	AChEI	BTM and SAM based organogel implants, subcutaneous administration	Preclinical rodent model	[195]

Aβ: Amyloid β; AD: Alzheimer’s disease; PLGA: Polylactide-co-glycolide; CNTF: Ciliary neurotrophic factor; AChEI: Acetylcholinesterase inhibitors; MAO-B: Monoamine oxidase B; NMDA: N-methyl-D-aspartate; GSK-3: Glycogen synthase kinase 3; PEG: Polyethylene glycol; PBCA: Polybutylcyanoacrylate; BTM: N-behenoyl L-tyrosine methylester; SAM: N-stearoyl L-alanine methylester.

Table 2 Current market status and ongoing clinical investigation for Alzheimer's disease therapeutics

Active	Mechanism of action	Drug delivery route	Clinical status	Ref.
Approved drugs
Tacrine (Cognex®)	AChEI	Oral	USFDA approved	[205]
Donepezil (Aricept®)	AChEI	Oral	USFDA approved
Galantamine (Razadyne, Reminyl®)	AChEI	Oral	USFDA approved
Rivastigmine (Exelon®)	AChEI	Transdermal patch	USFDA approved
Memantine (Namenda, Axura®, Ebixa®)	NMDA receptor inhibitor, glutaminergic system modifier	Oral	USFDA approved
Drugs under clinical investigation
EHT-0202	α-secretase activator	Oral	Phase 2	[29]
CTS-21166	β-secretase inhibitor	Oral	Phase 2	[35]
MK-0752	γ-secretase inhibitor	Oral	Phase 2	[29,36]
Immunoglobulin	AD immune activity	Intravenous	Phase 2	[170]
Omega-3-fatty acid treatment, nutritional supplement, physical exercise and cognitive stimulation	AD symptomatic management	Oral	Phase 3	[199]
Cerebrolysin and AChEI	Neirotropic, AChEI	Oral	Phase 4	[200,201]
Alzhemed™	Activity Aβ aggregation inhibitor	Oral (dietary supplement)	Phase 3	[206]

USFDA: United States Food and Drug Administration; AChEI: Acetylcholinesterase inhibitors; NMDA: N-methyl-D-aspartate; AD: Alzheimer’s disease.