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.