Hypoglycemic medicines in the treatment of Alzheimer’s disease: Pathophysiological links between AD and glucose metabolism

Abstract

Alzheimer’s Disease (AD) is a global chronic disease in adults with beta-amyloid (Aβ) deposits and hyperphosphorylated tau protein as the pathologic characteristics. Although the exact etiology of AD is still not fully elucidated, aberrant metabolism including insulin signaling and mitochondria dysfunction plays an important role in the development of AD. Binding to insulin receptor substrates, insulin can transport through the blood-brain barrier (BBB), thus mediating insulin signaling pathways to regulate physiological functions. Impaired insulin signaling pathways, including PI3K/Akt/GSK3β and MAPK pathways, could cause damage to the brain in the pathogenesis of AD. Mitochondrial dysfunction and overexpression of TXNIP could also be causative links between AD and DM. Some antidiabetic medicines may have benefits in the treatment of AD. Metformin can be beneficial for cognition improvement in AD patients, although results from clinical trials were inconsistent. Exendin-4 may affect AD in animal models but there is a lack of clinical trials. Liraglutide and dulaglutide could also benefit AD patients in adequate clinical studies but not semaglutide. Dipeptidyl peptidase IV inhibitors (DPP4is) such as saxagliptin, vildagliptin, linagliptin, and sitagliptin could boost cognitive function in animal models. And SGLT2 inhibitors such as empagliflozin and dapagliflozin were also considerably protective against new-onset dementia in T2DM patients. Insulin therapy is a promising therapy but some studies indicated that it may increase the risk of AD. Herbal medicines are helpful for cognitive function and neuroprotection in the brain. For example, polyphenols, alkaloids, glycosides, and flavonoids have protective benefits in cognition function and glucose metabolism. Focusing on glucose metabolism, we summarized the pharmacological mechanism of hypoglycemic drugs and herbal medicines. New treatment approaches including antidiabetic synthesized drugs and herbal medicines would be provided to patients with AD. More clinical trials are needed to produce definite evidence for the effectiveness of hypoglycemic medications.

Dapagliflozin Ameliorates Cognitive Impairment in Aluminum-Chloride-Induced Alzheimer’s Disease via Modulation of AMPK/mTOR, Oxidative Stress and Glucose Metabolism

“…It was reported that amino acids activate AMPK concurrently with mTOR [ 86 ]. However, another study showed that dapagliflozin enhanced AMPK and reduced mTOR [ 20 ]. This may be attributed to the different animal models, as the current study used AlCl 3 -induced AD, while the other study used a D-galactose Alzheimer’s rat model.…”

“…The mechanism of this SGLT2i beneficial effect on cognition was associated with reduced cerebral OS [ 19 ]. As a result, there is mounting evidence that SGLT2is have neuroprotective potential [ 20 ]. Second, our study highlighted the effect of dapagliflozin on glucose transporters and glycolytic enzymes, which was an additional mechanism to its neuroprotective effect reported before.…”

Prospects of antidiabetic drugs in the treatment of neurodegenerative disease

“…[182] Although originally designed to block glucose reabsorption in the kidneys, some SGLT-2 inhibitors, such as empagliflozin, have shown promise in preclinical studies for NDs. [183] Despite their generally low lipophilicity, which makes it challenging for them to cross the BBB, they may still offer neuroprotection through indirect mechanisms such as anti-inflammatory effects. Current studies are actively exploring ways to modify the molecular structure of these drugs, potentially enhancing their ability to penetrate the BBB.…”

“…These changes were correlated with improvements in cognitive functions, such as the ability to remember and learn, as assessed by the novel object recognition and Morris water maze tests [182] . Although originally designed to block glucose reabsorption in the kidneys, some SGLT‐2 inhibitors, such as empagliflozin, have shown promise in preclinical studies for NDs [183] . Despite their generally low lipophilicity, which makes it challenging for them to cross the BBB, they may still offer neuroprotection through indirect mechanisms such as anti‐inflammatory effects.…”

Lowering glucose enhances BACE1 activity and Aβ generation in mouse brain slice cultures

“…Both oxidative stress and inflammation are characteristics of AD, and are known to increase BACE1 expression and activity [37][38][39]. Similarly, there are links between oxidative stress and inflammation with hypoglycaemia [40]. BACE1, due to its role in Aβ generation, has become a potential target as a treatment for AD.…”