Neurodegeneration

Alzheimer’s Disease (AD) is a degenerative neurological disorder, accounting for 60-80% of dementia.72 AD affects up to one third of the population aged > 65 years, making it the fifth leading cause of death globally.73 Currently no drug exists to treat or slow down the development of AD. Instead, patients use drugs such as cholinesterase inhibitors and glutamate inhibitors to prevent the breakdown of acetylcholine and the overexcitation of neurons to amend their impaired cognitive functions.74–77
Applying metformin to treat AD stems from the widely observed association between AD and type 2 diabetes mellitus (T2DM). In 20 non-diabetic AD patients, treatment with metformin for 8 weeks resulted in improved cognitive functions (Koenig, Mechanic-Hamilton et al.).78 Nonetheless, a larger study that analyzed data from 7,086 dementia patients and matching number of healthy controls from the United Kingdom-based General Practice Research Database (GPRD) concluded otherwise; Individuals who did not receive any drug for diabetes (AOR=0.88, 95% CI=0.71–1.10) or those who took antidiabetic drugs (AOR=1.03, 95% CI=0.90–1.19) had a similar risk of developing AD as individuals without diabetes (AOR=1). Furthermore, patients who had been exposed to various anti-diabetic drugs and had received more than 60 prescriptions of metformin had increased the risk of developing AD (AOR=1.71, 95% CI=1.12-2.60), which was attributed to the production of A-β peptides, a hallmark for AD. However, the increased risk was not confirmed in patients who had taken metformin exclusively (AOR=1.00, 95% CI=0.55-1.81, >30 prescriptions), and there was no trend of increasing risk of AD with increasing number of metformin prescriptions.79 The increased production of A-β peptides caused by metformin was explained on cell cultures of primary cortical neurons and N2a neuroblastoma cells expressing human amyloid precursor protein (APP). Metformin upregulates the transcription of β-secretase, which cleaves APP into A-β peptides. Intriguingly, metformin combined with insulin reduced A-β peptide levels.80 In another study which diabetes model mice were used to evaluate AD-like brain changes and the effect of metformin on those changes, metformin attenuated the increase of total tau, phospho-tau, and activated JNK, a tau kinase, in the mice. Metformin also attenuated the decrease of synaptophysin and preserved the neural structures, but did not improve spatial learning and memory abilities.81 These studies together suggest that having taken metformin in the past does not reduce the risk of AD, but metformin used with insulin may be an effective short-term treatment.
Dysregulated mTOR activity and autophagy have been observed in patients with early Alzheimer’s disease.82 AD and mTOR’s connection has also been shown in a genome wide association study (GWAS), in which it identified 5 significant SNPs (rs6723868, rs30986, rs27709, rs26840, rs27648) that had to do with cerebellar age acceleration, defined to be negative when the epigenetic age is less than the chronological age (Table 2). Correlating the SNPs with mRNA levels of neighboring genes found genes that overlapped with those related to AD, age related macular degeneration, and Parkinson’s disease (PD). Among them, the gene MLST8 was significantly correlated with cerebellar age acceleration, and MLST8 is an integral part of the mTOR complexes.83 Hence, the mTOR inhibitor rapamycin has also been investigated to treat AD. Mice with increased mTOR activity had higher levels of tau and Aβlevels.84Administrating rapamycin to young 3xTg-AD mice induced mTOR-mediated autophagy and reduced Aβ and tau levels.85Nonetheless, rapamycin could only accelerate autophagy of tau and plaques before their formation: a significant reduction of tau and plaques was observed when treating AD mice at 2 months with rapamycin while at 15 months the treatment had no such effect.86Moreover, administering rapamycin to APOE4 mutant carrier mice, a transgenic AD mice model, resulted in restored cerebral blood flow and maintenance of blood-brain barrier integrity, pointing to rapamycin’s beneficial role in reducing vascular progression in AD.87
PD is known for tremors, difficulty in walking, and muscle rigidity in its patients due to dysfunction of the motor system.88PD affects around 1% of people aged > 60 years.89 Loss of dopaminergic neurons is characteristic of PD and leads to a decreased amount of dopamine as well as imbalance between dopamine and acetylcholine. According to the acetylcholine-dopamine balance hypothesis, over-activation of cholinergic system activity causes motor and cognitive disturbances. Hence, the current PD drugs either provide more dopamine or reduce the amount of acetylcholine to restore the balance, working as a remedy instead of neuroprotective agents.90–92
PD, diabetes, and dementia share the disorder of mitochondrial bioenergetics and abnormal protein folding in their pathogenesis, and several studies have found metformin to alleviate PD. An analysis of a cohort of 800,000 people from the Taiwan National Health Insurance database showed that having T2DM increased the risk of PD 2.2-fold, and metformin-inclusive sulfonylurea therapy reduced the risk (HR=0.78 relative to diabetes-free, 95% CI=0.61-1.01).93 The reason has to do with metformin’s ability to reduce α-synuclein release, a component of the Lewy bodies and Lewy neurites that are characteristic of PD. MPTP, a prodrug to the neurotoxin MPP+, was used to damage the mice dopaminergic neurons, leading to astroglial activation, which increased release of α-synuclein. Then metformin mitigated astroglial activation and promoted methylation of protein phosphatase 2A (PP2A), helping α-synuclein dephosphorylation. AMPK activation by metformin also increased ATP production in mitochondria and restored mitochondria function. However, the timing and dosage of metformin was also critical. When MPTP and metformin were given in the same day, 75% lethality ensued in the mice. Although metformin increased the levels of two neurotrophic factors BDNF and GDNF, high dosage (400 mg/kg) killed all the mice.94,95 In another study, metformin rescued tumor necrosis factor type 1 receptor associated protein (TRAP1) mutation associated changes in mitochondrial protein balance. TRAP1 is a protein associated with stress sensing in mitochondria, and its absence due to mutation has been identified to increase the risk for PD. Metformin reversed elevated mitochondrial respiration, reduced mitochondrial membrane potential, and imbalance of nuclear and mitochondrial protein production caused by the loss of TRAP1.96 In summary, metformin intervenes the pathogenesis of PD by preserving neurons, reducing inflammation, and protecting mitochondria functions. It is a promising new help for PD patients, but further studies are still needed to understand the influence of dosage and timing.