Early microglial accumulation in Alzheimer's disease (AD) delays disease progression by promoting clearance of ␤-amyloid (A␤) before formation of senile plaques. However, persistent A␤ accumulation despite increasing microglial numbers suggests that the ability of microglia to clear A␤ may decrease with age and progression of AD pathology. To determine the effects of aging and A␤ deposition on microglial ability to clear A␤, we used quantitative PCR to analyze gene expression in freshly isolated adult microglia from 1.5-, 3-, 8-, and 14-month-old transgenic PS1-APP mice, an established mouse model of AD, and from their nontransgenic littermates. We found that microglia from old PS1-APP mice, but not from younger mice, have a twofold to fivefold decrease in expression of the A␤-binding scavenger receptors scavenger receptor A (SRA), CD36, and RAGE (receptor for advanced-glycosylation endproducts), and the A␤-degrading enzymes insulysin, neprilysin, and MMP9, compared with their littermate controls. In contrast, PS1-APP microglia had a 2.5-fold increase in the proinflammatory cytokines IL-1␤ (interleukin-1␤) and tumor necrosis factor ␣ (TNF␣), suggesting that there is an inverse correlation between cytokine production and A␤ clearance. In support of this possibility, we found that incubation of cultured N9 mouse microglia with TNF␣ decreased the expression of SRA and CD36 and reduced A␤ uptake. Our data indicate that, although early microglial recruitment promotes A␤ clearance and is neuroprotective in AD, as disease progresses, proinflammatory cytokines produced in response to A␤ deposition downregulate genes involved in A␤ clearance and promote A␤ accumulation, therefore contributing to neurodegeneration. Antiinflammatory therapy for AD should take this dichotomous microglial role into consideration.

Highlights d Ab and tau work together to cause behavioral and transcriptional deficits in mice d In mice with Ab and tau, glial gene expression increases and synaptic genes decrease d Tau is present in synaptic terminals in APP/PS1+Tau mice and human Alzheimer brain d In mice, lowering tau levels improves cognition and restores gene expression

CX3CR1 is a chemokine receptor expressed on microglia that binds Fractalkine (CX3CL1) and regulates microglial recruitment to sites of neuroinflammation. Full deletion of CX3CR1 in mouse models of Alzheimer's disease have opposing effects on amyloid-β and tau pathologies raising concerns about the benefits of targeting CX3CR1 for treatment of this disease. Since most therapies achieve only partial blockade of their targets, we investigated the effects of partial CX3CR1 deficiency on the development and progression of amyloid-β deposition in the PS1-APP Alzheimer's mouse model. We generated PS1-APP mice heterozygous for CX3CR1 (PS1-APP-CX3CR1+/−) and analyzed these mice for Alzheimer's-like pathology. We found that partial CX3CR1 deficiency was associated with a significant reduction in Aβ levels and in senile-like plaque load in the brain as compared with age-matched PS1-APP mice. Reduced Aβ level in the brain was associated with improved cognitive function. Levels of the neuronal-expressed Aβ-degrading enzymes insulysin and matrix metalloproteinase 9, which are reduced in the brains of regular PS1-APP mice, were significantly higher in PS1-APP-CX3CR1+/− mice. Our data indicate that lowering CX3CR1 levels or partially inhibiting its activity in the brain may be a therapeutic strategy to increase neuronal Aβ clearance, reduce Aβ levels and delay progression of Alzheimer's-Like disease. Our findings also suggest a novel pathway where microglial CX3CR1 can regulates gene expression in neurons.

Synaptic dysfunction and loss is the strongest pathological correlate of cognitive decline in Alzheimer's disease (AD) with increasing evidence implicating neuropathological tau protein in this process. Despite the knowledge that tau spreads through defined synaptic circuits, it is currently unknown whether synapse loss occurs before the accumulation of tau or as a consequence. To address this, we have used array tomography to examine an rTgTauEC mouse model expressing a P301L human tau transgene and a transgene labeling cytoplasm red (tdTomato) and presynaptic terminals green (Synaptophysin‐EGFP). All transgenes are restricted primarily to the entorhinal cortex using the neuropsin promotor to drive tTA expression. It has previously been shown that rTgTauEC mice exhibit neuronal loss in the entorhinal cortex and synapse density loss in the middle molecular layer (MML) of the dentate gyrus at 24 months of age. Here, we observed the density of tau‐expressing and total presynapses, and the spread of tau into the postsynapse in the MML of 3–6, 9, and 18 month old red–green‐rTgTauEC mice. We observe no loss of synapse density in the MML up to 18 months even in axons expressing tau. Despite the maintenance of synapse density, we see spread of human tau from presynaptic terminals to postsynaptic compartments in the MML at very early ages, indicating that the spread of tau through neural circuits is not due to the degeneration of axon terminals and is an early feature of the disease process.

Vicarious trial-and-errors (VTEs) are back-and-forth movements of the head exhibited by rodents and other animals when faced with a decision. These behaviors have recently been associated with prospective sweeps of hippocampal place cell firing, and thus may reflect a rodent model of deliberative decision-making. The aim of the current study was to test whether the hippocampus is essential for VTEs in a spatial memory task and in a simple visual discrimination (VD) task. We found that lesions of the hippocampus with ibotenic acid produced a significant impairment in the accuracy of choices in a serial spatial reversal (SR) task. In terms of VTEs, whereas sham-lesioned animals engaged in more VTE behavior prior to identifying the location of the reward as opposed to repeated trials after it had been located, the lesioned animals failed to show this difference. In contrast, damage to the hippocampus had no effect on acquisition of a VD or on the VTEs seen in this task. For both lesion and sham-lesion animals, adding an additional choice to the VD increased the number of VTEs and decreased the accuracy of choices. Together, these results suggest that the hippocampus may be specifically involved in VTE behavior during spatial decision making.

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SummaryOne of the key knowledge gaps blocking development of effective therapeutics for Alzheimer's disease (AD) is the lack of understanding of how amyloid beta (Aß) and tau cooperate in causing disease phenotypes. Within a mouse tau deficient background, we probed the molecular, cellular and behavioural disruption triggered by wild-type human tau's influence on human Aß-induced pathology.We find that Aß and tau work cooperatively to cause a hyperactivity phenotype and to cause downregulation of gene transcription including many involved in synaptic function. In both our mouse model and in human post-mortem tissue, we observe accumulation of pathological tau in synapses, supporting the potential importance of synaptic tau. Importantly, tau depletion in the mice, initiated after behavioural deficits emerge, was found to correct behavioural deficits, reduce synaptic tau levels, and substantially reverse transcriptional perturbations, suggesting that lowering tau levels, particularly at the synapse, may be beneficial in AD.. CC-BY 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/393405 doi: bioRxiv preprint first posted online Aug. 16, 2018; 2 Highlights -Expression of human familial Alzheimer's associated mutant amyloid precursor protein and presenillin 1 with wild-type human tau in the absence of endogenous tau in a novel MAPT-AD mouse model results in behavioural deficits and downregulation of genes involved in synaptic function -Tau is present in pre and postsynaptic terminals in MAPT-AD mice and human AD brain. In mice, lowering synaptic tau levels was associated with improved cognition and recovered gene expression.-These data suggest that Aß and tau act cooperatively in impairing synaptic function and that lowering tau at synapses could be a beneficial therapeutic approach in AD.

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