Targeting neuroinflammation in Alzheimer's disease

Abstract

Almost 47 million people suffer from dementia worldwide, with an estimated new case diagnosed every 3.2 seconds. Alzheimer's disease (AD) accounts for approximately 60%-80% of all dementia cases. Given this evidence, it is clear dementia represents one of the greatest global public health challenges. Currently used drugs alleviate the symptoms of AD but do not treat the underlying causes of dementia. Hence, a worldwide quest is under way to find new treatments to stop, slow, or even prevent AD. Besides the classic targets of the oldest therapies, represented by cholinergic and glutamatergic systems, β-amyloid (Aβ) plaques, and tau tangles, new therapeutic approaches have other targets. One of the newest and most promising strategies is the control of reactive gliosis, a multicellular response to brain injury. This phenomenon occurs as a consequence of a persistent glial activation, which leads to cellular dysfunctions and neuroinflammation. Reactive gliosis is now considered a key abnormality in the AD brain. It has been demonstrated that reactive astrocytes surround both Aβ plaques and tau tangles. In this condition, glial cells lose some of their homeostatic functions and acquire a proinflammatory phenotype amplifying neuronal damage. So, molecules that are able to restore their physiological functions and control the neuroinflammatory process offer new therapeutic opportunities for this devastating disease. In this review, we describe the role of neuroinflammation in the AD pathogenesis and progression and then provide an overview of the recent research with the aim of developing new therapies to treat this disorder.

Keywords: Alzheimer’s disease; astrocyte; microglia; reactive gliosis.

Figure 1

Schematic representation of glial activation. Notes: As a result of brain damage (eg, brain trauma, ischemia, Aβ accumulation, NFTs, etc) microglia and astrocytes acquire a so-called reactive phenotype losing their physiological functions. Morphofunctional changes, loss of three-dimensional network, and neurovascular unit alterations contribute to cause a homeostatic imbalance. Moreover, after activation, these cells produce a wide range of cytokines and proinflammatory mediators, leading to chronic inflammation. Even if the initial intent of these modifications is reparative, such long-lasting and uncontrolled activation causes further neurodegeneration. Abbreviations: ROS, reactive oxygen species, NO, nitric oxide; Aβ, β-.amyloid; NFTs, neurofibrillary tangles; BBB, blood–brain barrier.

Figure 2

Integrated pathways between glial activation, neuroinflammation, and neuronal death after brain injury. Notes: Whenever a brain injury occurs, glial activation takes place with the aim of removing injurious stimuli. To this aim, activated cells undergo a series of morphofunctional changes and acquire a reactive phenotype. Activation causes, among other things, glial hypertrophy, astrocyte endfeet retraction, and gain of amoeboid microglial structure. These changes, if not stopped, can induce synaptic dysfunction, homeostatic imbalance, neurovascular unit dysfunction, loss of three-dimensional network, and BBB dysfunction. In addition, reactive microglia and astrocytes release a wide range of proinflammatory mediators aimed at removing the primary injury. The occurrence of a reactive state is very probably a protective response. However, uncontrolled and prolonged activation goes beyond physiological control, and detrimental effects override the beneficial ones. Solid arrows indicate complete pathways. Dashed arrows indicate pathways that that occur partially or do not. Abbreviations: BBB, blood–brain barrier; Aβ, β-amyloid; NFTs, neurofibrillary tangles; SCARA-1, scavenger receptor class A Type 1; SCARB-1, scavenger receptor class B member 1; RAGE, receptor for advanced glycation end product; GPCRs, G protein-coupled receptors; FPR2, formyl peptide receptor 2; CMKLR1, chemokine-like receptor 1; TLRs, toll-like receptors; IL, interleukin; IFN-γ, interferon-γ; GM-CSF, granulocyte-macrophage colony-stimulating factor; NO, nitric oxide; ROS, reactive oxygen species; SPs, senile plaques; IBA1, ionized calcium-binding adapter molecule 1; CD, cluster of differentiation.