Pathological mechanisms and therapeutic strategies for Alzheimer’s disease

Abstract

Alzheimer’s disease is a rather complex neurodegenerative disease, which is attributed to a combination of multiple factors. Among the many pathological pathways, synaptic dysfunctions, such as synapses loss and deficits in synaptic plasticity, were thought to be strongly associated with cognitive decline. The deficiencies in various sorts of neurotransmissions are responsible for the multifarious neurodegenerative symptoms in Alzheimer’s disease, for example, the cholinergic and glutamatergic deficits for cognitive decline, the excitatory and inhibitory neurotransmission dyshomeostasis for synaptic plasticity deficits and epileptiform symptoms, and the monoamine neurotransmission for neuropsychiatric symptoms. Amyloid cascade hypothesis is the most popular pathological theory to explain Alzheimer’s disease pathogenesis and attracts considerable attention. Multiple lines of genetic and pathological evidence support the predominant role of amyloid beta in Alzheimer’s disease pathology. Neurofibrillary tangles assembled by microtubule-associated protein tau are other important histopathological characteristics in Alzheimer’s disease brains. Cascade of tau toxicity was proved to lead to neuron damage, neuroinflammation and oxidative stress in brain. Ageing is the main risk factor of neurodegenerative diseases, and is associated with inflammation, oxidative stress, reduced metabolism, endocrine insufficiencies and organ failures. These aging related risk factors were also proved to be some of the risk factors contributing to Alzheimer’s disease. In Alzheimer’s disease drug development, many good therapeutic strategies have been investigated in clinical evaluations. However, complex mechanism of Alzheimer’s disease and the interplay among different pathological factors call for the come out of all-powerful therapies with multiple curing functions. This review seeks to summarize some of the representative treatments targeting different pathological pathways currently under clinical evaluations. Multi-target therapies as an emerging strategy for Alzheimer’s disease treatment will be highlighted.

Neurotransmitters—Key Factors in Neurological and Neurodegenerative Disorders of the Central Nervous System

“…Glutamate is a predominant excitatory NT in the CNS, which can be produced from glutamine and represents the precursor of GABA [ 11 , 12 , 13 ]. Glutamate is liberated from presynaptic neurons into the synaptic cleft, which leads to the activation of N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors that further mediate calcium and sodium influxes in postsynaptic neurons.…”

“…Glutamatergic neurotransmission is highly important in long-term potentiation, contributing to cognitive functions, such as learning and memory formation [ 11 , 13 ]. Moreover, it is also responsible for many motor, sensory, and autonomic activities [ 15 ].…”

“…Moreover, the excess of monoamines remaining in the synaptic cleft is further degraded by monoamine oxidase (EC 1.4.3.4.) or catechol-O-methyltransferase (EC 2.1.1.6) or undergoes reuptake into the presynaptic terminal by monoamine transporters [ 11 ]. Severe neurological diseases (e.g., AD, PD, HD, schizophrenia) can occur when this equilibrium is dysregulated [ 56 , 57 ].…”

“…From the cholinergic presynaptic neurons, acetylcholine is transported to synaptic vesicles via vesicular acetylcholine transporters, and, after the depolarization of neurons, it is released into the synaptic cleft. Further, it enables neurotransmission by binding to acetylcholine receptors [ 11 ].…”

“…Moreover, deficiencies in various NTs have been noted to be responsible for neurodegenerative symptoms of AD: cognitive decline has been linked to cholinergic and glutamatergic deficits, synaptic plasticity deficits, and epileptiform symptoms have been associated with excitatory and inhibitory neurotransmission dyshomeostasis, while neuropsychiatric symptoms are closely related to monoamine neurotransmission modifications [ 11 ].…”