Clusterin secreted from astrocyte promotes excitatory synaptic transmission and ameliorates Alzheimer’s disease neuropathology

Abstract

Background Genome-wide association studies have established clusterin (CLU) as a genetic modifier for late-onset Alzheimer’s disease (AD). Both protective and risk alleles have been identified which may be associated with its expression levels. However, the physiological function of clusterin in the central nervous system remains largely unknown. Methods We examined Clu expression in mouse brains by immunohistochemistry and high-resolution imaging. We performed electrophysiological recordings and morphological analysis of dendritic spines in wild-type and Clu knockout mice. We tested synaptic function of astrocytic Clu using neuron-glia co-cultures and by AAV-mediated astroglial Clu expression in vivo. Finally, we investigated the role of astrocytic Clu on synaptic properties and amyloid pathology in 5xFAD transgenic mouse model of AD. Results We show that astrocyte secreted Clu co-localizes with presynaptic puncta of excitatory neurons. Loss of Clu led to impaired presynaptic function and reduced spine density in vivo. Neurons co-cultured with Clu-overexpressing astrocytes or treated with conditioned media from HEK293 cells transfected with Clu displayed enhanced excitatory neurotransmission. AAV-mediated astroglial Clu expression promoted excitatory neurotransmission in wild-type mice and rescued synaptic deficits in Clu knockout mice. Overexpression of Clu in the astrocytes of 5xFAD mice led to reduced Aβ pathology and fully rescued the synaptic deficits. Conclusion We identify Clu as an astrocyte-derived synaptogenic and anti-amyloid factor; the combination of these activities may influence the progression of late-onset AD.

FoxO3 deficiency in cortical astrocytes leads to impaired lipid metabolism and aggravated amyloid pathology

“…We then prepared adeno‐associated virus (AAV) particles expressing either GFP or a FLAG‐tagged FOXO3 under the GFAP promoter. As we have shown previously (Chen et al, 2021; Martini‐Stoica et al, 2018), intracerebroventricular (i.c.v) injection of AAV‐GFP or AAV‐FOXO3 to the cKO mice at postnatal day 3 (P3) and analysis at 3 months documented efficient astrocyte expression (Figure a, b) and restoration of FoxO3 expression in AAV‐FOXO3‐injected mice (Figure c). GFAP and C3 immunostaining revealed a significant decrease in cortical astrogliosis in the cKO mice with AAV‐FOXO3 administration compared to AAV‐GFP‐injected controls (Figure 1n–p).…”

“…For AAV injections, postnatal day 3 pups were anesthetized via hypothermia and injected i.c.v. free‐hand with 2.5 × 10 10 viral particles per side using a 28‐gauge needle attached to a Hamilton syringe as described previously (Chen et al, 2021 ; Martini‐Stoica et al, 2018 ). RNA sequencing of total RNA was performed using the Illumina platform.…”

Neuronal–glial communication perturbations in murine SOD1G93A spinal cord

“…Up-regulation of Grin2c , Sparc , and Clu was identified; these genes regulate glutamate-induced signal transduction and synapse function (Fig. 4a , Supplementary Data 1 ) 35 – 38 . The strongest gene-set alterations within astrocytes were related to complement activation (Fig.…”

“…Astrocyte Sparc has been shown to increase in response to extracellular glutamate levels and regulate levels of neuronal post-synaptic glutamate receptors 38 . Clu has been implicated in regulating synaptic function 35 .…”

Microglia and Astrocytes in Alzheimer’s Disease in the Context of the Aberrant Copper Homeostasis Hypothesis

“…It is believed that astrocyte-induced Aβ clearance may be stimulated by an increment in the expression of proteases, such as neprilysin, insulin-degrading enzyme, endothelin-converting enzyme (ECE), and metalloproteases [ 68 , 69 , 70 , 71 ]. There are also several complementary mechanisms related to the secretion of extracellular chaperones by astrocytes, including ApoE, apolipoprotein J (Apo J)/clusterin, α2-macroglobulin (α2-M), and α1-21 antichymotrypsin (ACT), which participate in Aβ clearance across the BBB [ 54 , 72 , 73 , 74 ]. The A2 phenotype displays protective features by upregulating several neurotrophic factors, such as S100 calcium-binding protein A10 (S100A10) and brain-derived neurotrophic factor [ 51 , 53 ].…”