The Toll Route to Structural Brain Plasticity

Abstract

The human brain can change throughout life as we learn, adapt and age. A balance between structural brain plasticity and homeostasis characterizes the healthy brain, and the breakdown of this balance accompanies brain tumors, psychiatric disorders, and neurodegenerative diseases. However, the link between circuit modifications, brain function, and behavior remains unclear. Importantly, the underlying molecular mechanisms are starting to be uncovered. The fruit-fly Drosophila is a very powerful model organism to discover molecular mechanisms and test them in vivo. There is abundant evidence that the Drosophila brain is plastic, and here we travel from the pioneering discoveries to recent findings and progress on molecular mechanisms. We pause on the recent discovery that, in the Drosophila central nervous system, Toll receptors—which bind neurotrophin ligands—regulate structural plasticity during development and in the adult brain. Through their topographic distribution across distinct brain modules and their ability to switch between alternative signaling outcomes, Tolls can enable the brain to translate experience into structural change. Intriguing similarities between Toll and mammalian Toll-like receptor function could reveal a further involvement in structural plasticity, degeneration, and disease in the human brain.

Pós COVID na Atenção Primária à Saúde e Ambulatorial Especializada: Reunindo evidências para o Sistema Único de Saúde e à Plataforma Clínica Global da OMS

“…Além disso, uma coorte com 86 pacientes que se recuperaram de COVID-19 leve mostrou que o genótipo GG TLR4-2604G>A (rs10759931) está associado com piores desfechos cognitivos (66). De fato, a literatura tem destacado o papel dos TLRs, particularmente em astrócitos, em infecções e doenças no SNC, propondo uma ligação entre a sinalização mediada por estes receptores com a patogênese de doenças neurodegenerativas (37,67).…”

Toll‐like receptors in pathogenesis of neurodegenerative diseases and their therapeutic potential

“… 2 , 16 , 17 TLRs have also been shown to influence neural development and cognitive function. 16 This review paper summarized findings demonstrating the function of TLRs in neurodegenerative diseases.…”

“…9,10,15 TLR-mediated neuroinflammation has been linked to a wide range of infectious and noninfectious neurological and neurodegenerative CNS conditions. 2,16,17 TLRs have also been shown to influence neural development and cognitive function. 16 This review paper summarized findings demonstrating the function of TLRs in neurodegenerative diseases.…”

Drosophila Toll-9 is induced by aging and neurodegeneration to modulate stress signaling and its deficiency exacerbates tau-mediated neurodegeneration

“… 6 , 26 However, many of these Toll receptors do not play roles in immunity but rather in neurodevelopment. 27 , 28 , 29 , 30 Among them, Toll-9 is most closely related to mammalian TLRs at a structural level, 18 , 31 and according to the Drosophila RNAi Screening Center 20 (DRSC) Integrative Ortholog Prediction Tool ( https://www.flyrnai.org/cgi-bin/DRSC_orthologs.pl ), TLR10 shows the highest similarity with fly Toll-9 among ten human TLRs. TLRs are type-I transmembrane receptors composed of an extracellular leucine-rich repeats domain, a single transmembrane domain, and an intracellular region called the Toll-interleukin receptor domain.…”

“…A series of recent reports highlight critical roles of Drosophila Toll receptors in central nervous system (CNS) structural plasticity 27 , 28 and cell death. 24 , 25 , 37 In addition, mammalian TLRs are implicated in age-related neurodegenerative diseases.…”