Table 2.

Summary of representative of preclinical and clinical studies on the efficacy of antidiabetic, insulin-sensitizing drugs on multiple aspects of AD pathology.

Compound	Potential Pathway	Study Design	Reference
DA5-CH	Reduces tau phosphorylation and normalizes theta rhythm	Injected intracerebroventricula (ICV), streptozotocin on rat	[89]
DA-JC1	Antagonizing circadian rhythm disorders induced by Aβ31–35	ICV, amyloid(31–35) AD model	[90]
DA5-CH	Improved of hippocampal synaptic plasticity and activation of the PI3K/AKT signaling pathway	APP/PS1 mouse model of AD	[91]
DA-CH3	Reduced ER stress and apoptotic signaling, reduced amyloid plaque load in the brain	APP/PS1 mouse model of AD	[92]
Insulin	Prevention of Aβ oligomer induced synapse loss and insulin receptor reduction, amelioration of PKR-mediated ER stress	Rat hippocampal neuronal cultures	[93,94]
Insulin	AD patients that are not ε4 carriers have reduced sensitivity to insulin, effecting cognitive performance	AD patients homozygous or not for the ApoE-ε4 allele and normal subjects intravenously injected	[95]
Insulin	Improved verbal memory in MCI AD ε4-subjects after acute insulin administration, but not in ε4 carriers	AD patients homozygous or not for the ApoE-ε4 allele, MCI patients and most subjects intranasally administrated	[96,97]
Insulin	Chromic intranasal insulin doses enhanced selective attention, retention of new information and functional status of MCI and early AD subjects	AD patients, MCI patients and normal subjects intranasally administrated	[98]
Insulin	Only women presented improved working memory after treatment	Healthy men and woman intranasally administrated	[99]
Liraglutide	Reduction of tau phosphorylation; protection of insulin reception and synapse loss in a c-AMP dependent manner	Cynomolgus monkeys ICV with Aβ oligomer	[100]
Liraglutide	Improvement of memory deficits in novel object recognition test and fear conditioning	Swiss mice injected ICV with Aβ oligomer	[100]
Liraglutide	Restored memory deficits in object recognition test and Morris water maze; enhanced LTP; reduced microglial activation; diminished Aβ plaque load	APP/PSEN1 mice	[101,102]
Exendin-4	Decrease in the inhibitory phosphorylation of Ser312IRS1, Ser66IRS1 of INK, while restoring activating Tyr465 IRS1 phosphorylation	Rat hippocampal neural cultures	[69]
Exendin-4	Improvement of spatial memory in the Morris water maze; reduced amyloid plaque LOAD	APP/PS1 mice	[69]
Exedin4- Liraglutide	eIF2α phosphorylation reduction	Rat hippocampal neural cultures, APP/PS1 mice, cynomolgus monkeys injected ICV with Aβ oligomer	[94]
GLP-1 Exendin-4	Reduction of neural excitotoxicity	Rat hippocampal neural cultures, rats injected on the basal nucleus with ibotenic acid	[103]
Rosiglitazone	Reversal of memory deficits in objects recognition test and the Morris water maze; Aβ levels reduction	AD transgenic mice J20 line	[104]