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Histological examination of the hippocampus and cortex of CP2-treated APP/PS1 mice using 4G8 antibody revealed a significant reduction in Aβ plaques compared to untreated littermates (Fig. 4a, b). Biochemical analysis conducted using sequential extraction of brain tissue showed that CP2 treatment reduced total Aβ levels (Fig. 4c). While soluble Aβ was increased (Fig. 4d, e), levels of insoluble peptides were significantly decreased (Fig. 4f). Improved proteostasis could be promoted by autophagic degradation associated with AMPK activation and inhibition of the activity of glycogen synthase kinase-3 (GSK3β), whose hyperactivation in AD is directly linked to Aβ pathology30,31. Indeed, CP2-dependent AMPK activation increased inhibitory phosphorylation of GSK3β and promoted the expression of proteins associated with lysosomal biogenesis and autophagy, including the transcription factor EB (TFEB), lysosomal-associated membrane protein 1 (LAMP-1), and microtubule-associated protein light chain 3 (LC3B) (Fig. 4g, Supplementary Figs. 7, 8). These data further support the contention that CP2-induced autophagy is one of the neuroprotective pathways essential for Aβ clearance (Fig. 1d).
Synaptic loss is the best correlate of cognitive dysfunction in AD36. To determine whether augmented cognitive performance after CP2 treatment was associated with improved synaptic function, we analyzed excitatory postsynaptic potential (fEPSP) in the CA1 region in acute hippocampal slices of APP/PS1 and NTG mice measuring local field potential (Fig. 5)37. We initially recorded basal synaptic transmission and strength of post-synaptic responses to electrical stimulation of Schaffer collaterals (Fig. 5a). Activation of Schaffer collaterals revealed reduction of fiber volley amplitudes in APP/PS1 mice compared to NTG mice (Fig. 5b, c), which was partially restored by CP2 treatment (Fig. 5c).
Neurons of the locus coeruleus (LC) provide norepinephrine to the hippocampus, mediating memory and attention46. AD patients exhibit early neurodegeneration in the LC where severity of neuronal loss correlates with the duration of illness47. Neurodegeneration in the LC has been shown to affect Aβ and Tau aggregation, inflammation, synaptic function, neuronal metabolism, and BBB permeability48. Previously, we demonstrated that the degeneration of LC neurons in human AD is recapitulated in mouse models of cerebral amyloid49,50. In the current APP/PS1 mice, progressive loss of TH+ cortical afferents starts at 6 months of age (Fig. 7a, b; Supplementary Fig. 12a, c), followed by the loss of noradrenergic (TH+) neurons in the LC (Fig. 7c, d, Supplementary Fig. 12b, d). Consistent with the progressive loss of afferents, there was a reduction in the volume of TH+ neurons in APP/PS1 mice starting at 12 months of age (Fig. 7e, f). Analysis of 12 month old APP/PS1 mice that received CP2 treatment for 2 months (from 10 months of age) showed that CP2 did not impact neurodegeneration, since the cortical TH+ axon density, the number of TH+ neurons, and neuronal volumes were similar between vehicle-treated and CP2-treated subjects (Fig. 7b, d, f; 12-month-old group). In mice receiving CP2 for 10 months, further progression of neurodegeneration was completely halted by the CP2 treatment. Thus, cortical TH+ axon density, TH+ neuron number in LC, and TH+ neuronal volume in 20 month old CP2-treated APP/PS1 mice were comparable to those in 12 month old APP/PS1 mice (Fig. 7b, d, f; 20-month-old group). These data demonstrate that CP2 specifically protects the neuronal network in APP/PS1 mice, which might be associated with the reduction of Aβ accumulation and toxicity.
Among genes involved in the regulation of oxidative stress and apoptosis were G6pdx, BIRC3, TRIM30a, Trp53, and Mt3, all known to play a role in human disease (Supplementary Fig. 14e). Other important changes included global downregulation of the immune response by CP2 including the acute phase response, such as upregulation of SERPING1, interferon signaling (DDX58, FCGR1A, TRIM25, GBP5, TLR7, IFITM3, IFIT1, NLRC5, OASL2, IRGM1, IIGP1), and major histocompatibility complex (MHC) class II presentation (H2-DMa, H2-Q10, H2-Eb1, H2-Aa, PSMB8, PSMB9) (Supplementary Fig. 14e). Pathways upregulated by CP2 included dendritic spine maturation, axonal extension and guidance, and synaptic transmission (Supplementary Fig. 14f-g). The identified upregulated genes in dendrite morphogenesis pathways included the Down syndrome cell-adhesion molecule (DSCAM) (Supplementary Fig. 14f), which is involved in governing neurite arborization, mosaic tiling, and dendrite self-avoidance and BTB Domain Containing 3 (BTBD3), which has a role in dendritic guidance toward active axon terminals. Genes that mediate axonogenesis, including Ntng1 and Ntng2, and axonal guidance, were also upregulated in CP2-treated APP/PS1 mice (Supplementary Fig. 14g, Supplementary Fig. 13d). Additional genes upregulated by CP2 in APP/PS1 mice included those involved in synaptic transmission and synapse assembly and that are known to be downregulated in AD patients, including glutamate receptor 4 (GRIA4), which mediates fast synaptic excitatory neurotransmission; metabotropic glutamate receptor 7 and 2 (GRMN7 and GRM2), which facilitates the formation of LTP; Double C2 protein (Doc2a), which contributes to spontaneous excitatory and inhibitory release; and Neurexins1 (NRXN1), which facilitates formation of functional synaptic structures (Supplementary Figs. 13e, 14h). These data are consistent with the improved synaptic function in CP2-treated APP/PS1 mice (Fig. 5).
We next compared the 567 DEGs associated with CP2 treatment in APP/PS1 mice (Fig. 8a) with DEGs from females in the AMP-AD RNA-seq data collection. We found that 128 out of the total 567 overlapping mouse AD DEGs corresponded to human AD genes (Fig. 8c). CP2 treatment in APP/PS1 mice reversed the expression of 71 genes that were upregulated in both mouse and human AD (Supplementary Data 16). Functional enrichment analysis showed that these 71 genes were involved in the regulation of the immune processes, inflammation, response to reactive oxygen species, and TNF production (Fig. 8d, Supplementary Data 17). In contrast, CP2 reversed the expression of 57 deregulated genes that are involved in axonogenesis, glutamatergic synaptic transmission, nervous system development, and synapse assembly (Fig. 8c, e and Supplementary Data 18, 19). Taken together, these data demonstrate that AD-associated transcriptional and functional changes observed in our mouse model of AD are counteracted by CP2 treatment. CP2-treated APP/PS1 mice showed attenuated expression of a number of genes involved in neuroinflammatory processes, consistent with our observation of a decreased number of activated astrocytes and microglia. Moreover, CP2 treatment of APP/PS1 mice restored expression of genes involved in neurotransmission, dendritic morphology and axonal guidance and extension, which were linked to the restoration of hippocampal LTP and increased number of mature dendritic spines (Fig. 6). These data demonstrate that pathways improved by CP2 treatment in APP/PS1 mice comprise major pathways essential for therapeutic efficacy in AD patients.
AD is associated with early energy hypometabolism, synaptic and mitochondrial dysfunction, oxidative stress, inflammation, abnormal proteostasis and progressive neurodegeneration. Here, we demonstrate that mild energetic stress associated with partial inhibition of MCI induces activation of integrated stress-response mechanisms that attenuate effects of pathological pathways such as abnormal energy homeostasis, synaptic dysfunction, and inflammation, ultimately blocking neurodegeneration in a translational mouse model of AD, the APP/PS1 mice. The therapeutic efficacy achieved has translational relevance, as the intervention was started after the onset of Aβ neuropathology26, cognitive symptoms27, bioenergetic dysfunction28, and progressive neurodegeneration. Beneficial mechanisms affected by CP2 treatment in APP/PS1 mice overlap with signatures established in AD patients, females in particular, supporting the high translational potential of this approach. Major translational targets affected by CP2 treatment included the immune system response and multiple pathways involved in synaptic function and neurotransmission, which underlie early pathology in AD patients8. Since CP2 improved axonogenesis and dendritic spine morphology and function, it is feasible that this treatment could also induce neuronal regeneration.
The strength of our study is in the utilization of multiple early and late disease outcome measures in a mouse model of AD that closely mimics neuropathological mechanisms of human disease. In particular, we hypothesized that the general failure of the preclinical studies in mouse models of AD to predict outcomes of human clinical trials is related to the reliance on treatments of younger mice and a very limited set of neuropathological outcome measures. Thus, it is important that CP2 treatment of APP/PS1 mice was conducted when AD-like pathology, including progressive neurodegeneration, was well established and the broad array of measures, including advanced imaging techniques and translational biomarkers, were applied in vivo and in tissue, further supporting the ability to monitor therapeutic efficacy of this approach in humans. However, this study was limited only to female mice. 2ff7e9595c
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