Alzheimer's disease (AD), the most common type of dementia, is an irreversible and progressive neurodegenerative disorder causing cognitive and functional impairment. It is characterized by formation of protein aggregates and progressive loss of neurons in the central nervous system (CNS). The symptoms of AD include short-term memory loss, confusion, irritability, aggression and mood swings, progressing to long-term memory deficit, withdrawal from social interactions and subsequently a loss in higher central functioning.
Pathogenesis of Alzheimer's Disease
Historically, AD has been suggested to be caused by a loss of cholinergic neurons and a decrease in acetylcholine production. However, lack of efficacy of pharmacological treatments targeting the cholinergic system has led to declining popularity of this hypothesis.
The current model of AD pathogenesis involves the formation of two histopathological features in the CNS; neurofibrillary tangles (NFTs) and senile plaques.
NFTs are intracellular structures localized within neurons that are formed from paired helical filaments (PHFs). The core protein within PHFs is tau, a microtubule-associated protein that is hyperphosphorylated in the brains of AD sufferers. Tau hyperphosphorylation is an early event in AD pathogenesis and is mediated by cyclin-dependent kinase 5 (cdk5) and glycogen synthase kinase 3β (GSK-3β). Hyperphosphorylated tau can not be incorporated into microtubules and aggregates in neuronal cells, forming PHFs and subsequently NFTs.
Senile plaques are formed by deposits of amyloid fibrils in the extracellular environment of the brain. Amyloid fibrils are formed from the oligomerization of amyloid β (Aβ) peptides into insoluble polymers. Aβ peptides are formed from the proteolytic cleavage of amyloid precursor protein (APP) by α-, β- and γ-secretases into Aβ(1-40) and Aβ(1-42) proteins. Aβ(1-42) is much more fibrillogenic than Aβ(1-40), thus is the pathological form of the protein. Aβ(1-42) plaques accumulate in brain regions such as the cerebellum, striatum and thalamus, where they are implicated in the development of AD. Furthermore, abberant trafficking of APP by kinesin-I has a role in the development of this disease.
In AD, neuronal loss is caused by several mechanisms. Aβ peptides induce high levels of oxygen- and nitrogen-reactive species and reduce endogenous levels of antioxidants, which play a central role in the destruction of neurons. Oxidative damage to lipids and membrane proteins causes synaptic loss and white matter rarefraction, which are characteristics of AD. Aβ peptides increase the vulnerability of neurons to excitotoxicity through upregulation of ionotropic glutamate receptors, furthering oxidative damage and neural loss. Tau has been proposed to be an essential mediator in this process.
Reactive astrocytes and activated microglia surround senile plaques in AD and produce chemotatic factors and complement proteins. Aβ binds Cq1 and activates the complement-dependent membrane attack complex (MAC), causing local toxicity to neurons. In addition, neurotoxicity is mediated through induction of inflammatory mediators such as IL-1β and TNF-α. Neuronal apoptosis also occurs in AD and is induced by Aβ-activated caspase-2.
This progressive Aβ-mediated neuritic and synaptic injury alters neuronal homeostasis and is a contributing factor in the abnormal functioning of cdk5 and GSK-3β, which cause tau hyperphosphorylation. Thus, it is fair to conclude that Aβ plays an initiating role in the pathogenic AD cascade that results in altered tau metabolism.
There is no cure for AD. Current pharmacological interventions for AD are limited and mainly act to alleviate symptoms. They include acetylcholinesterase inhibitors, ionotropic glutamate receptor antagonists and antipsychotics. There is intense research into developing treatments for AD with some focusing on immunotherapy and vaccination against APP or Aβ, as well as development of ligands to the more conventional pharmacological targets.
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A potent, second-generation γ-secretase modulator that decreases Aβ(1-39), Aβ(1-40) and A(1-42), and increases Aβ(1-37).
A potent, orally available non-peptidic β-secretase (BACE1) inhibitor with IC50 of 239 nM in enzyme assays; demonstrates ∼10-fold selectivity over BACE2, and >50-fold over aspartyl proteases cathepsin D, pepsin, or renin; produces profound Aβ-lowering effects in vivo.
A potent γ-secretase inhibitor that has an IC50 value of 119 pM for reduction of Aβ levels in APP-transfected cell lines; dose dependently reduces Aβ(1-40) and Aβ(1-42) in the brain, CSF, and plasma of Tg2576 mice; reduces cortical Abeta(40) in young transgenic CRND8 mice with ED50 of 0.6 mg/kg, and produces significant thymus atrophy and intestinal goblet cell hyperplasia at higher doses (>3 mg/kg).
GIBH-130 is a novel inhibitor of neuroinflammation, suppresses the proinflammatory cytokine production in LPS-stimulated N9 microglial cells (IC50=3.4 nM); modulates the release of detrimental proinflammatory cytokines; exhibits in vivo efficacy of cognitive impairment in both β amyloid-induced and APP/PS1 double transgenic Alzheimer's murine models.
PF-04447943 is a potent, selective, brain penetrant, orally active PDE9A inhibitor with IC50 of 8.3 nM; displays high selectivity versus PDEs1-8 and 10-11 (>150-fold over PDE1C, IC50=1394 nM); significantly increases neurite outgrowth and synapse formation in cultured hippocampal neurons at 30-100 nM; enhances synaptic plasticity and cognitive function in rodents.
Crisdesalazine (AAD-2004, AAD2004) is a derivative of aspirin that inhibits microsomal PGE(2) synthase-1 (mPGES-1) activity in response to both LPS-treated BV2 cell with IC50 of 230 nM and recombinant human mPGES-1 protein with IC50 of 249 nM in vitro; blocked free radical production, PGE(2) formation, and microglial activation in the spinal cords in superoxide dismutase 1(G93A) transgenic mouse model of ALS, reduced autophagosome formation, axonopathy, and motor neuron degeneration, improving motor function and increasing life span, which is superior to riluzole or ibuprofen.
Nelonicline (ABT-126) is a potent, selective α7 nicotinic receptor (nAChR) partial agonist for the treatment of cognitive impairment with schizophrenia.
TAK-071 (TAK071) is a novel potent, selective, low cooperativity (α-value) positive allosteric modulator of muscarinic M1 receptor with inflection point of 2.7 nM in Ca2+ flux assays in CHO-K1 cells; displays >370-fold M1R selectivity over other muscarinic receptors; selectively induces afterdepolarization in prefrontal cortical pyramidal neurons significantly ameliorates scopolamine-induced cognitive deficits in rats combined with acetylcholinesterase inhibitor donepezil, with minimizing peripheral cholinergic side effects.
ASP3662 is a potent, selective, CNS-penetrable and orally active inhibitor of 11β-HSD1 with Ki of 5.3, 2.6 and 23 nM for human, mouse and rat 11β-HSD1, does not inhibit human 11β-HSD2 at 30 uM; demonstrates no appreciable binding affinity to or inhibition against 87 off-targets (adenosine receptors, adrenergic receptors, angiotensin receptors, calcium channels, 5-HT receptors etc.); inhibits the in vitro conversion of glucocorticoid from its inactive to active form in the brain and spinal cord; ameliorates mechanical allodynia in spinal nerve ligation (SNL) and streptozotocin-induced diabetic rats and thermal hyperalgesia in chronic constriction nerve injury rats.
An orally bioavailable small molecule inhibitor of RAGE; inhibits sRAGE from binding to RAGE ligands, S100b, amphoterin and carboxymethyl-lysine; has been shown to inhibit the binding of sRAGE to Aβ1-42 in a fluorescent polarization assay; reduces accumulation in the spleen of Aβ peptides and the expression of IL-6 and macrophage colony stimulating factor, reduces both inflammatory markers (TNF-α, TGF-β and IL-1) and CNS amyloid deposition.
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