Astrocytes as a Therapeutic Target in Alzheimer’s Disease–Comprehensive Review and Recent Developments

Abstract

Alzheimer’s disease (AD) is a frequent and disabling neurodegenerative disorder, in which astrocytes participate in several pathophysiological processes including neuroinflammation, excitotoxicity, oxidative stress and lipid metabolism (along with a critical role in apolipoprotein E function). Current evidence shows that astrocytes have both neuroprotective and neurotoxic effects depending on the disease stage and microenvironmental factors. Furthermore, astrocytes appear to be affected by the presence of amyloid-beta (Aβ), with alterations in calcium levels, gliotransmission and proinflammatory activity via RAGE-NF-κB pathway. In addition, astrocytes play an important role in the metabolism of tau and clearance of Aβ through the glymphatic system. In this review, we will discuss novel pharmacological and non-pharmacological treatments focused on astrocytes as therapeutic targets for AD. These interventions include effects on anti-inflammatory/antioxidant systems, glutamate activity, lipid metabolism, neurovascular coupling and glymphatic system, calcium dysregulation, and in the release of peptides which affects glial and neuronal function. According to the AD stage, these therapies may be of benefit in either preventing or delaying the progression of the disease.

A neuroinflamação da Doença de Alzheimer e sua correlação anatômica

“…Além disso, o TNF-α inibe a capacidade fagocítica microglial, ao mesmo tempo em que estimula a secreção de γ-secretase, portanto promovendo maiores formações de placas beta amiloides e, consequentemente, o desenvolvimento da cascata inflamatória no cérebro de pacientes com DA (10,18,19). Juntamente à micróglia, astrócitos também apresentam efeitos neuroprotetivos ou neurotóxicos, dependendo do estágio da doença (20,21). No início da DA, auxiliam na degradação de βA.…”

“…Sabe-se ainda, que, sob o ambiente pró-inflamatório, astrócitos acumulam em seu citoplasma proteína tau, comprometendo várias de suas funções celulares, isto é, sinalização de cálcio, clearance de glutamato, metabolismo energético, entre outras (20,48).…”

“…Acerca dessas células do SNC, no estágio inicial da doença, suas ações são benéficas, dispondo efeitos neuroprotetores. Todavia, com a evolução da DA, o processo neuroinflamatório é agravado pela ação dessas células, caracterizando-o como efeito neurotóxico, pela deposição de placas βA (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). O presente trabalho objetiva realizar uma revisão literária acerca da neuroinflamação da DA.…”

Current understanding of metal-dependent amyloid-β aggregation and toxicity

“…Very recently, lecanemab has been tested in the phase III clinical trial, demonstrating that it has better safety and efficacy than aducanumab. [7][8][9] In addition, there has been a call for the expansion or modification of the amyloid cascade hypothesis based on emerging evidence on the inter-relationship between A and other pathogenic elements found in AD-affected brains. 3,10,11 Given that high concentrations of metal ions [e.g., 0.4 mM for Cu(I/II) and 1.0 mM for Zn(II)] are observed in senile plaques mainly composed of A aggregates, metal ions and A are suggested to be mutually involved in the pathogenesis of AD.…”

“…Very recently, lecanemab was tested in the phase III clinical trial, demonstrating that it has better safety and efficacy than aducanumab. 7–9 In addition, there has been a call for the expansion or modification of the amyloid cascade hypothesis based on emerging evidence on the inter-relationship between Aβ and other pathogenic elements found in AD-affected brains. 3,10,11…”