Link between Diabetes and Alzheimer’s Disease Due to the Shared Amyloid Aggregation and Deposition Involving Both Neurodegenerative Changes and Neurovascular Damages
Abstract
:1. Socio-Economic Burden of Diabetes and Alzheimer’s Disease
2. Amyloid Formation as a Common Pathological Feature in both Diabetes and Alzheimer’s Disease
2.1. Relations between Diabetes and Alzheimer’s Disease
2.2. Amyloid Formation and Deposition Involving both Neurodegenerative Changes and Neurovascular Damage
- ▪
- Misplaced mutations of the APP, presenilin−1 (PSEN−1), and or presenilin−2 (PSEN−2) genes that may result in increased production of Aβ42 peptides throughout life in the dominant forms of AD or,
- ▪
- by impairing the Aβ peptide purification mechanisms that would favor the gradual increase of the Aβ42 peptide level in the brain in the case of non-dominant forms of AD.
2.3. Evidence from the Shared Pathological Traits
3. The Influence of Amyloid-β Aggregates on Diabetes Pathology and Islet Amyloid Polypeptide on Alzheimer’s Disease in Animal Models
4. Relevance of Molecular Interaction between Islet Amyloid Polypeptide and Amyloid-β Peptide for Novel Therapeutics
5. Concluding Remarks
Author Contributions
Funding
Conflicts of Interest
Abbreviations
References
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Diabetes | Insulin |
Biguanides: Metformin | |
Sulphonylureas: Glibenclamide, Glibornuride, Glipizide, Gliquidone, Glisoxepide, Glyclopyramide, Glimepiride | |
Alpha-glucosidase inhibitors: Acarbose, Miglitol, Voglibose | |
Incretins Dipeptidyl peptidase−4 inhibitors: Sitagliptin, Saxagliptin, Linagliptin, Alogliptin Glucagon-like peptide−1 receptor agonists: Exenatide, Liraglutide, Albiglutide, Dulaglutide | |
Thiazolidinediones: Pioglitazone, Rosiglitazone | |
SGLT2 Inhibitors: Empagliflozin, Canagliflozin, Dapagliflozin, Ipragliflozin | |
Meglitinides: Repaglinide, Nateglinide | |
Amylin analog: Pramlintide | |
Alzheimer’s Disease | Cholinesterase inhibitors: Tacrine, Donepezil, Rivastigmine, Galantamine |
N-methyl-D-aspartate receptor: Memantine |
Antidiabetic Medication | Experimental Model | Findings | References |
---|---|---|---|
Biguanides | |||
Metformin | mouse neuroblastoma cell lines under sustained hyperinsulinemic conditions treated with different concentrations of metformin (0.4–3.2 mM) | resensitization of insulin signaling; prevention of the molecular and pathological alterations detected in AD neurons | [130] |
transgenic APPswe/PSd1E9 mouse model of AD; intraperitoneal delivery of 200 mg/kg metformin for 14 days | amelioration of spatial memory deficits, neural cellular proliferation; in the cortex and hippocampus, reduction of local inflammation, decrease of Aβ plaque deposition | [119] | |
PDAPP (J9) mouse model of AD; 350 mg/kg/day metformin delivered in drinking water for several months | attenuation of memory impairment in female subjects and intensification of it in males | [131] | |
longitudinal aging study in adults with diabetes | long-term metformin therapy (over 6 years) could diminish the risk of developing AD | [132] | |
case-control study, older adults with an incident diagnosis of AD; 1–9, 10–29, 30–59, or ≥60 metformin prescriptions | long-term treatment (60 or more prescriptions) has been correlated with a slight augmented risk of developing AD | [133] | |
Sulphonylureas | |||
Glibenclamide | Aβ25–35-induced rat AD model; 6 mg/kg/day of glibenclamide for 20 days by gavage | reduction of Aβ25–35-treated behavioral anomalies | [134] |
Thiazolidinediones | |||
Pioglitazone | meta-analysis of randomized clinical trials; 15 to 30 mg of pioglitazone, as adjunct therapy for AD | doses of 15 to 30 mg pioglitazone but not 45 mg improve cognitive capacity | [135] |
transgenic APPswe/PSEN1dE9 AD mouse model; combined therapy with 0.03 mg/kg/day of leptin intranasal delivery + intraperitoneal administration of 10 mg/kg/day pioglitazone for 2 weeks | decrease of spatial memory impairments and brain Aβ levels | [122] | |
APPV717I transgenic mice, a model for AD; acute 7 days gavage therapy with 40 mg/kg/day of pioglitazone | reduction of soluble Aβ1–42 peptide levels by 27% and glial inflammation | [125] | |
controlled trial in cases with mild Alzheimer’s disease and an accompanying diagnosis of diabetes; daily doses of 15–30 mg pioglitazone for 6 months | cognitive and functional improvements and stabilization of the disease in diabetics with AD | [136] | |
controlled pilot trial in individuals with AD without diabetes; daily 45 mg of pioglitazone | 18 months of pioglitazone therapy were well tolerated by patients, but no important efficacy data were detected | [137] | |
Rosiglitazone | meta-analysis of randomized clinical trials; 2 to 8 mg of rosiglitazone, as adjunct therapy for mild to moderate AD patients | pro-cognitive effects | [135] |
pilot study that randomized individuals with AD or amnestic mild cognitive damage | better delayed recall and selective attention | [138] | |
large study in population with mild to moderate AD; 2, 4, or 8 mg of rosiglitazone for 6 months | in week 24 an improvement (−2.9 points) of cognition in apolipoprotein Eε4-negative people treated with 8 mg of rosiglitazone was registered | [139] | |
phase III trials of rosiglitazone in AD; 2 mg or 8 mg rosiglitazone for 48 weeks, as adjunctive agent to ongoing acetylcholine esterase inhibitors | rosiglitazone did not lead to an improvement in cognition or overall function | [140] | |
Glucagon-like peptide−1 receptor agonists | |||
Lixisenatide | transgenic APPswe/PSd1E9 mouse model of AD; intraperitoneal injection with 1 or 10 nmol/kg of compound for 10 weeks | several biomarkers have been improved such as learning, inflammation, or plate loading | [129] |
cell culture, 100μM of lixisenatide were applied 24 h before Aβ25–35 application rat model of AD; 5 nmol/μL of lixisenatide before intrahippocampal application of Aβ25–35 (5 nmol/μL) | reversal Aβ25–35-triggered cytotoxicity, normalization of intracellular calcium levels prevention of memory loss caused by amyloid intracerebroventricular injection | [141] | |
transgenic APP/PS1/tau mouse model of AD; daily intraperitoneal injection of 10 nmol/kg lixisenatide for 60 days | reduction of amyloid plaques, neuroinflammation, and neurofibrillary tangles | [142] | |
Dulaglutide | intracerebral injection of streptozotocin-induced mouse AD-like condition; 0.6 mg/kg/week of dulaglutide with intraperitoneal delivery for 4 weeks | amelioration of learning and memory deficits | [143] |
Liraglutide | transgenic APPswe/PSd1E9 mouse model of AD; intraperitoneal injection with 2.5 or 25 nmol/kg of drug for 10 weeks | improvement of learning, reduction of amyloid plaque deposits by 40%–50%, and decrease inflammatory response | [129] |
methylglyoxal-induced mouse Alzheimer-like condition; daily subcutaneous administration of 25 nmol/kg liraglutide for 2 months | attenuation of hippocampal damage and cognitive deficits in C57BL/6J mice | [144] | |
cell culture; liraglutide (300 nm) was added to cultures 40 min before Aβ oligomers Aβ oligomers-induced AD mouse model; daily intraperitoneal injections of liraglutide (25 nmol/kg) for 7 days Aβ oligomer-induced non-human primate model of AD; subcutaneous delivery of liraglutide (0.006 mg/kg/day for the first week and 0.012 mg/kg thereafter) for 24 days | reduction of Aβ oligomer-induced synaptotoxicity, protective effects on synapses; prevention and reversal of cognitive abnormalities, and insulin receptor loss produced by intracerebroventricular injection of Aβ oligomers; the agent was less effective, but still provided partial protection against insulin resistance loss; synapses and phosphorylation of tau | [121] | |
Aβ protein-induced rat model of AD; 2 μL liraglutide trough intrahippocampal administration | liraglutide pre-therapy remarkably protected against Aβ-induced damage of spatial memory and long-term potentiation | [145] | |
transgenic 3xTg-AD female mice; 0.2 mg/kg/day of liraglutide, intraperitoneal injections | reduction of cortical Aβ1–42 levels, partial attenuation of cerebral estradiol, inflammation, and oxidative/nitrosative stress | [146] | |
a pilot clinical trial in AD patients lasting 26 weeks; in the first week, the drug was daily delivered subcutaneously at a dose of 0.6 mg; hereafter 1.2 mg daily for another week before finally increasing to 1.8 mg daily | prevention of brain glucose metabolism decline; there were no important cognitive changes compared with placebo group | [147] | |
Dipeptidyl peptidase−4 inhibitors | |||
Saxagliptin | intracerebral injection of streptozotocin-induced rat model of AD; 0.25, 0.5, and 1 mg/kg of saxagliptin administered orally for 60 days | reduction of amyloid plaque formation, a marked decrease of Aβ42 level, and phosphorylation of tau protein; total reversal of cognitive impairments | [148] |
Vildagliptin | intracerebral injection of streptozotocin-induced rat model of AD; daily oral doses of 2.5, 5, and 10 mg/kg vildagliptin for 30 days | attenuation of Aβ, phosphorylation of tau protein, and inflammatory markers | [149] |
Aβ protein-induced rat model of AD; daily gavage of 5 or 10 mg/kg vildagliptin for 4 weeks | anti-apoptotic effect, attenuation of memory abnormalities, reduction of tau phosphorylation, and increase of neurotrophic protein expression | [150] | |
streptozotocin-induced rat diabetes model associated cognitive decline; daily gavage of 5 mg/kg vildagliptin for 4 weeks | prevention of memory impairment and diminution of apoptosis in hippocampal neurons | [151] | |
Sitagliptin | APP/PS1 AD mice model; 20 mg/kg/day of sitagliptin for an 8-weeks period | protective effect of cognitive function, reduction of amyloid plaque deposits | [152] |
transgenic APPswe/PSd1E9 mouse model of AD; daily gavage of 5, 10, and 20 mg/kg sitagliptin for 12 weeks | much more obvious effects for the 20 mg/kg sitagliptin dose—reduction of nitrosative stress and inflammation markers; an important diminution in the number and area of APP and Aβ deposition | [153] | |
Linagliptin | 3xTg-AD mouse model of AD; daily oral administration of 5, 10, and 20 mg/kg linagliptin for 8 weeks | improvement of cognitive performance; reduction of Aβ42 levels, but not Aβ40; diminution of tau phosphorylation and neuroinflammation | [154] |
human neuroblastoma SK-N-MC cell culture; exposure to 10 to 100 μM linagliptin for 24 h | protection of cells against Aβ-induced intracellular reactive oxygen species accumulation and mitochondria dysfunction | [155] | |
Amylin analog | |||
Pramlintide | SAMP8 mice, a model of sporadic AD; subcutaneous infusion of 0.24 mg/kg/day pramlintide for 5 weeks | may improve memory, decrease neuroinflammation, and reduce oxidative stress | [156] |
Sodium-glucose cotransporter 2 (SGLT−2) inhibitors | |||
Canagliflozin | scopolamine-induced rat model of memory impairment; daily oral gavage of 10 mg/kg for 2 weeks | improvement of memory dysfunction | [157] |
Insulin analogues | |||
intracerebral injection of streptozotocin rat model of cognitive decline; 0.5 units = 12 nmol of detemir | alleviating cognitive dysfunction with a significant increase in learning ability; change in insulin degrading enzyme, insulin receptor, and somatostatin | [158] | |
patients with early AD; intranasal administration of 20 or 40 IU insulin | facilitation of verbal memory recall in memory-impaired ɛ4− patients; no influence on glucose or plasma insulin levels | [159] | |
patients with early AD; intranasal administration of 20 or 40 IU insulin for 21 days | improvement of attention, functional status, and verbal memory; modulation of Aβ peptide | [87] | |
placebo-controlled pilot clinical trial in people with AD; intranasal delivery of 20 or 40 IU insulin for 4 months | improvement of cognition and functional ability compared to control group | [160] | |
clinical trial; 20 or 40 IU of insulin detemir for 21 days, intranasal administration in AD | therapy effect for the memory composite outcome for the 40 IU patients, influenced by the APOE status | [161] |
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Stanciu, G.D.; Bild, V.; Ababei, D.C.; Rusu, R.N.; Cobzaru, A.; Paduraru, L.; Bulea, D. Link between Diabetes and Alzheimer’s Disease Due to the Shared Amyloid Aggregation and Deposition Involving Both Neurodegenerative Changes and Neurovascular Damages. J. Clin. Med. 2020, 9, 1713. https://doi.org/10.3390/jcm9061713
Stanciu GD, Bild V, Ababei DC, Rusu RN, Cobzaru A, Paduraru L, Bulea D. Link between Diabetes and Alzheimer’s Disease Due to the Shared Amyloid Aggregation and Deposition Involving Both Neurodegenerative Changes and Neurovascular Damages. Journal of Clinical Medicine. 2020; 9(6):1713. https://doi.org/10.3390/jcm9061713
Chicago/Turabian StyleStanciu, Gabriela Dumitrita, Veronica Bild, Daniela Carmen Ababei, Razvan Nicolae Rusu, Alina Cobzaru, Luminita Paduraru, and Delia Bulea. 2020. "Link between Diabetes and Alzheimer’s Disease Due to the Shared Amyloid Aggregation and Deposition Involving Both Neurodegenerative Changes and Neurovascular Damages" Journal of Clinical Medicine 9, no. 6: 1713. https://doi.org/10.3390/jcm9061713
APA StyleStanciu, G. D., Bild, V., Ababei, D. C., Rusu, R. N., Cobzaru, A., Paduraru, L., & Bulea, D. (2020). Link between Diabetes and Alzheimer’s Disease Due to the Shared Amyloid Aggregation and Deposition Involving Both Neurodegenerative Changes and Neurovascular Damages. Journal of Clinical Medicine, 9(6), 1713. https://doi.org/10.3390/jcm9061713