The "aged garlic extract:" (AGE) and one of its active ingredients S-allyl-L-cysteine (SAC) as potential preventive and therapeutic agents for Alzheimer's disease (AD)

Abstract

Alzheimer's disease (AD) is the most common form of dementia in the older people and 7(th) leading cause of death in the United States. Deposition of amyloid-beta (Aβ) plaques, hyperphosphorylation of microtubule associated protein tau (MAPT), neuroinflammation and cholinergic neuron loss are the major hallmarks of AD. Deposition of Aβ peptides, which takes place years before the clinical onset of the disease can trigger hyperphophorylation of tau proteins and neuroinflammation, and the latter is thought to be primarily involved in neuronal and synaptic damage seen in AD. To date, four cholinesterase inhibitors or ChEI (tacrine, rivastigmine, donepezil and galantamine) and a partial NMDA receptor antagonist (memantine) are the only approved treatment options for AD. However, these drugs fail to completely cure the disease, which warrants a search for newer class of targets that would eventually lead to effective drugs for the treatment of AD. In addition to selected pharmacological agents, botanical and medicinal plant extracts are also being investigated. Apart from its culinary use, garlic (Allium sativum) is being used to treat several ailments like cancer and diabetes. Herein we have discussed the effects of a specific 'Aged Garlic Extract' (AGE) and one of its active ingredients, S-allyl-L-cysteine (SAC) in restricting several pathological cascades related to the synaptic degeneration and neuroinflammatory pathways associated with AD. Thus, based on the reported positive preliminary results reviewed herein, further research is required to develop the full potential of AGE and/or SAC into an effective preventative strategy for AD.

Fig. (1)

The schematic diagram shows APP processing by secretase enzymes. APP is a transmembrane protein consists of 695–771 amino acids. The major or primary cleavage pathway of APP is shown in the left, where it is initially cleaved by α-secretase enzyme. This enzyme cleaves APP within its Aβ domain; hence it precludes the generation of Aβ peptides and termed as ‘non-amyloidogenic pathway’. The second cleavage was carried out by γ-secretase. As shown in the figure, α-secretase pathway produces sAPPα and a small P3 fragment. In contrast, the minor or β-secretase pathway is shown at the right side of the figure. Proteolytic cleavage of APP molecule by β-secretase and subsequent cleavage by γ-secretase produce sAPPβ and Aβ peptides and the latter is pathognomonic for AD. Generated Aβ can form aggregates and deposits as neuritic plaques within the brain parenchyma.

Fig. (2)

The schematic shows potential roles of AGE and SAC in ameliorating APP and Aβ related pathologies in the context of AD. AGE treatment was shown to decrease the levels of APP in Alzheimer’s Tg mice (refer text), which was reflected in decreased Aβ levels. Further, SAC was shown to possess potential effects in disaggregating Aβ peptides. Deposited Aβ can activate caspases, and particularly caspase 3 activation can take a leading role in neuronal loss and disrupting synaptic structures. AGE was shown to inactivate caspase 3 in APP-Tg mice. Further, increased levels of insulin in the brain have neurotrophic as well as Aβ clearing function. The latter is thought to be carried out by up-regulation of insulin degrading enzyme (IDE). AGE is a natural secretagogue of insulin and indirectly capable of reducing brain Aβ load. It was observed that neuronal damage by deposited Aβ can be due to induction of endoplasmic reticulum (ER) stress, which is attenuated by garlic compounds, such as AGE and SAC. Further, hyperlipidemia can cause enhanced Aβ production (see the text), and AGE treatment can substantially reduce total cholesterol levels by inhibiting HMGCoA- reductase, the rate limiting enzyme of cholesterol biosynthesis.

Fig. (3)

Hyperphosphorylation of tau is one of the hallmarks of AD. Apart from reduction in Aβ-load, preventing excessive phosphorylation of tau is also considered to be a rational strategy for the treatment of AD. AGE and SAC treatments to the APP-Tg mice (as described in Fig.2) decreased the levels of hyperphosphorylated tau in the brain of treated animals versus untreated Tg mice [16]. Mechanistically, AGE and SAC were observed to inhibit the enzyme GSK-3β, a prime enzyme responsible for the hyperphosphorylation of tau. Deposited Aβ can also initiate hyperphosphorylation of tau protein. In this aspect, AGE and SAC’s Aβ lowering properties would be helpful in reducing hyperphosphorylation of tau. Further, activated microglia can release a series of cytochemokines, which also play important roles in hyperphosphorylation of tau. AGE and SAC treatment in APP-Tg mice were shown to decrease activated microglia load in treated Tg mice versus untreated Tg controls [16]. AGE and SAC treatment can also be beneficial in tauopathies by decreasing serum cholesterol levels.

Fig. (4)

AGE and SAC can modulate different inflammatory pathways related to the pathogenesis of AD. Microglial activation by deposited Aβ peptides can be abridged by their potential roles in reducing the brain Aβ load. Further, SAC was found to inhibit the activation of the pro-inflammatory transcription factor NFκB. The latter plays an important role in the production of several cytochemokines. Activated NFκB is also responsible in generation of Aβ from APP. As mentioned in the text, apart from producing cytochemokines, activated microglia can produce ROS, leading to widespread neuronal damage. AGE and SAC treatments were independently shown to increase the production of glutathione (GSH), an important molecule to neutralize ROS. AGE treatment was also shown to have PPAR-γ agonistic property and the latter is believed to modulate expression of several pro-inflammatory genes. It was postulated that cholinergic neurons are most vulnerable by inflammation associated with AD. Notably, the increased HACU and ChAT activity, as observed by AGE and SAC treatment, is able to preserve cholinergic neurons from ROS or cytochemokines-mediated damage.