Conditional BDNF delivery from astrocytes rescues memory deficits, spine density and synaptic properties in the 5xFAD mouse model of Alzheimer disease

Abstract

It has been well documented that neurotrophins, including brain-derived neurotrophic factor (BDNF), are severely affected in Alzheimer's disease (AD), but their administration faces a myriad of technical challenges. Here we took advantage of the early astrogliosis observed in an amyloid mouse model of AD (5xFAD) and used it as an internal sensor to administer BDNF conditionally and locally. We first demonstrate the relevance of BDNF release from astrocytes by evaluating the effects of coculturing WT neurons and BDNF-deficient astrocytes. Next, we crossed 5xFAD mice with pGFAP:BDNF mice (only males were used) to create 5xFAD mice that overexpress BDNF when and where astrogliosis is initiated (5xF:pGB mice). We evaluated the behavioral phenotype of these mice. We first found that BDNF from astrocytes is crucial for dendrite outgrowth and spine number in cultured WT neurons. Double-mutant 5xF:pGB mice displayed improvements in cognitive tasks compared with 5xFAD littermates. In these mice, there was a rescue of BDNF/TrkB downstream signaling activity associated with an improvement of dendritic spine density and morphology. Clusters of synaptic markers, PSD-95 and synaptophysin, were also recovered in 5xF:pGB compared with 5xFAD mice as well as the number of presynaptic vesicles at excitatory synapses. Additionally, experimentally evoked LTP in vivo was increased in 5xF:pGB mice. The beneficial effects of conditional BDNF production and local delivery at the location of active neuropathology highlight the potential to use endogenous biomarkers with early onset, such as astrogliosis, as regulators of neurotrophic therapy in AD.Recent evidence places astrocytes as pivotal players during synaptic plasticity and memory processes. In the present work, we first provide evidence that astrocytes are essential for neuronal morphology via BDNF release. We then crossed transgenic mice (5xFAD mice) with the transgenic pGFAP-BDNF mice, which express BDNF under the GFAP promoter. The resultant doublemutant mice 5xF:pGB mice displayed a full rescue of hippocampal BDNF loss and related signaling compared with 5xFAD mice and a significant and specific improvement in all the evaluated cognitive tasks. These improvements did not correlate with amelioration of ␤ amyloid load or hippocampal adult neurogenesis rate but were accompanied by a dramatic recovery of structural and functional synaptic plasticity.

Astrocyte remodeling in the beneficial effects of long-term voluntary exercise in Alzheimer’s disease

“…Evidence for the involvement of astrocytes in BDNF-mediated cognitive outcomes is numerous. For example, astrocytes expressing a truncated form of TrkB T1 respond to application of BNDF by releasing Ca 2+ from intracellular space [ 82 ], astrocytes respond to increased BDNF by expression of TrkB receptors [ 83 ], astrocytes themselves produce the BDNF protein as it was shown in our study and in previous works [ 84 , 85 ], and BDNF released from astrocytes is crucial for dendrite spine density and morphology [ 86 ]. Importantly, BDNF has been shown to regulate astrocytic morphology through TrkB-T1 receptors located specifically in GFAP+ astrocytes [ 26 , 87 ].…”

VGF-derived peptide TLQP-21 modulates microglial function through C3aR1 signaling pathways and reduces neuropathology in 5xFAD mice

“…Because reduced levels of protein markers of synaptic health (e.g. PSD-95) are generally not observed in 5xFAD until they are at least 6-months of age [34,63,107,108], future experiments will be required to determine whether TLQP-21mediated rescue of amyloid and microglial phenotypes in male 5xFAD mice at 5 months of age is associated with memory improvement and reduced synaptic damage as the TLQP-21-treated mice age. Importantly, we find that human TLQP-21 activates human microglia with similar outcomes to the activation of murine microglia by mouse TLQP-21, confirming the potential relevance of the mechanisms and pathways that we described for human disease.…”

Astrocytic BDNF and TrkB regulate severity and neuronal activity in mouse models of temporal lobe epilepsy

“…pGFAP-BDNF mice display worse phenotype and increased neuronal death in the lithium-pilocarpine model of TLE First, since it has been widely demonstrated that BDNF is expressed and released by astrocytes [20][21][22][23] , we aimed to study the role of the neurotrophin produced by astrocytes in a TLE model by using wild-type (WT) mice and the pGFAP-BDNF transgenic mice as a gain-of-BDNFfunction approach. In these mice, BDNF is overexpressed only under pathological conditions 20,21 . To do so, first we subjected pGFAP-BDNF mice and their WT controls to the lithium-pilocarpine model (Fig.…”

“…Previous studies have shown that in vitro and in vivo astrocytes produce and release BDNF [20][21][22][23] . To functionally explore the influence of astrocytic BDNF over the neuronal population response in an epileptic context we used a loss-and a gain-of-BDNF-function approach Data were analyzed by two-way ANOVA followed by Bonferroni's test.…”