Forest Biomass as a Promising Source of Bioactive Essential Oil and Phenolic Compounds for Alzheimer's Disease Therapy

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting elderly people worldwide. Currently, there are no effective treatments for AD able to prevent disease progression, highlighting the urgency of finding new therapeutic strategies to stop or delay this pathology. Several plants exhibit potential as source of safe and multi-target new therapeutic molecules for AD treatment. Meanwhile, Eucalyptus globulus extracts revealed important pharmacological activities, namely antioxidant and anti-inflammatory properties, which can contribute to the reported neuroprotective effects. This review summarizes the chemical composition of essential oil (EO) and phenolic extracts obtained from Eucalyptus globulus leaves, disclosing major compounds and their effects on AD-relevant pathological features, including deposition of amyloid-β (Aβ) in senile plaques and hyperphosphorylated tau in neurofibrillary tangles (NFTs), abnormalities in GABAergic, cholinergic and glutamatergic neurotransmission, inflammation, and oxidative stress. In general, 1,8-cineole is the major compound identified in EO, and ellagic acid, quercetin, and rutin were described as main compounds in phenolic extracts from Eucalyptus globulus leaves. EO and phenolic extracts, and especially their major compounds, were found to prevent several pathological cellular processes and to improve cognitive function in AD animal models. Therefore, Eucalyptus globulus leaves are a relevant source of biological active and safe molecules that could be used as raw material for nutraceuticals and plant-based medicinal products useful for AD prevention and treatment.

Keywords: Alzheimer’s disease; essential oil; eucalyptus; phenolic extracts.

Figure 1

Major compounds found in essential oils and phenolic extracts obtained from E. globulus leaves.

Figure 2

Effect of compounds obtained from E. globulus leaves in the amyloidogenic pathway and in the formation of amyloid-β (Aβ) in AD. The amyloidogenic pathway is initiated with the enzymatic breakdown of amyloid precursor protein (APP) by β-secretase enzyme followed by catalytic cleavage of APP by γ-secretase to originate non-soluble protein or Aβ. Aβ oligomerization and accumulation leads to synaptic dysfunction and neurodegeneration.

Figure 3

Effect of compounds obtained from E. globulus leaves on tau aggregation and formation of neurofibrillary tangles (NFTs) in AD. Irregular phosphorylation of tau proteins destabilizes microtubules, leading to the formation of insoluble tau oligomers, which then accumulate to generate protomers. Then, two twisted protomers originate paired helical filaments, which after aggregation lead to the formation of NFTs. These intracellular structures are involved in synaptic and neuronal dysfunction, thus contributing to cognitive decline in AD.

Figure 4

Effect of compounds obtained from E. globulus leaves in oxidative stress and mitochondrial damage in AD. Aβ oligomers can insert the plasma membrane originating pores by which Ca²⁺ pass into the cytoplasm. Aβ can also interact with metal ions (Fe²⁺ and Cu⁺) to generate reactive oxygen species (ROS), which cause membrane lipid peroxidation. As consequence, the membrane turns depolarized, and voltage-dependent Ca²⁺ channels (VDCC) and glutamate receptor-associated channels (in particular NMDAR, N-methyl-D-aspartate receptor) open increasing cytoplasmic Ca²⁺ content. Additionally, Aβ overproduction can cause mitochondrial damage, which culminates in ROS accumulation and ATP depletion that can impair axonal transport consequently originating abnormal mitochondrial dynamics and promoting neurotransmission deficits. ATP depletion can also lead to ionic alterations in the cytosol due to dysfunction of ATP-dependent ion channels. Moreover, ROS accumulation affects the mitochondrial permeability transition pore (MPTP), which further potentiates mitochondrial damage due to Ca²⁺ overload and inhibition of the electron transport chain. ROS increase also promotes damage to proteins, namely DNA and RNA.

Figure 5

Effect of compounds obtained from E. globulus leaves on neuroinflammation in AD. A vicious circle between Aβ and tau accumulation in the brain, microglia activation, and release of pro-inflammatory cytokines culminates in neuronal death in AD.

Figure 6

Effect of compounds obtained from E. globulus leaves on cholinesterase activity in AD. Synthesis of acetylcholine (ACh) neurotransmitter from acetyl coenzyme A (Acetyl CoA) and choline (Ch) occurs by the action of the enzyme choline acetyltransferase (ChAT) in the presynaptic terminal. Acetylcholine is released in the synaptic cleft, where it can activate both muscarinic (mAChR) and nicotinic (nAChR) receptors. Acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) break acetylcholine into choline and acetate. ACh levels are low in AD brains and cholinergic neurotransmission in impaired. AChE and BChE inhibitors correct these deficits increasing the amount of ACh that remains in the synaptic cleft and interacts with postsynaptic receptors.

Figure 7

Effect of compounds obtained from E. globulus leaves on inhibitory (A) and excitatory (B) synapses in AD. (A) The inhibitory γ-aminobutyric acid (GABA) synapse. GABA is synthesized from glutamate by the glutamic acid decarboxylase enzymes in the presynaptic terminal of GABAergic neuron. The vesicular GABA transporter packs GABA into vesicles, which, after release in the synaptic cleft, binds GABA_A receptors localized on the postsynaptic neuron. The reuptake of GABA into the presynaptic axon stops the GABA action in the synapse. GABA levels are significantly reduced in AD patients as well as the GABA_A receptor density. (B) The excitatory glutamate synapse. Glutamine is converted to glutamate via glutaminase in the presynaptic terminal of glutamatergic neuron, and the vesicular glutamate transporter packs glutamate into vesicles. After glutamate release in the synaptic cleft, it acts on glutamate receptors localized on the postsynaptic neuron. The excitatory amino acid transporters (EAATs) present in nearby astrocytes clear the glutamate from the synaptic cleft. Glutamate is converted to glutamine via glutamine synthetase in astrocytes before being transported to presynaptic neurons. In AD, Aβ oligomers affect extrasynaptic N-methyl-D-aspartate (NMDA) receptors enriched in NR2B subunits, leading to an excessive activation and consequently to an excess of Ca²⁺ accumulation in the post-synaptic cell.

Figure 8

Effect of compounds obtained from E. globulus leaves in the AD-associated memory and learning impairment.