Alzheimer's brain inoculation in Aβ-plaque bearing mice: synaptic loss is linked to tau seeding and low microglial activity

Abstract

Alzheimers disease (AD) is characterized by intracerebral accumulations of extracellular amyloid-{beta} (A{beta}) plaques and intracellular tau pathology that spread in the brain. Tau lesions occur in the form of neuropil threads, neurofibrillary tangles, and neuritic plaques i.e. tau aggregates within neurites surrounding A{beta} deposits. The cascade of events linking these lesions and synaptic or memory impairments are still debated. Intracerebral infusion of human AD brain extracts in A{beta} plaque-bearing mice that do not overexpress pathological tau proteins induces tau pathologies following heterotopic seeding of mouse tau protein. There is however little information regarding the downstream events including synaptic or cognitive repercussions of tau pathology induction in these models. In the current study, human AD brain extracts (ADbe) and control-brain extracts (Ctrlbe) were infused in the hippocampus of A{beta} plaque-bearing APPswe/PS1dE9 mice. Memory, synaptic density, as well as A{beta} plaque and tau aggregate loads, microgliosis, astrogliosis at the inoculation site and in connected regions (perirhinal/entorhinal cortex) were evaluated 4 and 8 months post-inoculation. ADbe inoculation induced memory deficit. It increased deposition of A{beta} plaques close to the inoculation site. Tau pathology was also induced in ADbe-inoculated mice. Neuropil threads and neurofibrillary tangles occurred next to the inoculation site and spread to connected regions notably the perirhinal/entorhinal cortex. Neuritic plaque pathology was detected in both ADbe- and Ctrlbe- inoculated animals but ADbe inoculation increased the severity close and at distance of the inoculation site. Finally, ADbe inoculation reduced synaptic density close to the inoculation site and in connected regions as the perirhinal/entorhinal cortex. Synaptic impairments were correlated with increased severity of neuritic plaques but not of other tau lesions or A{beta} lesions, which suggests that neuritic plaques are a culprit for synaptic loss. Synaptic density was also associated with microglial load. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=182 HEIGHT=200 SRC="FIGDIR/small/438654v4_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@791f29org.highwire.dtl.DTLVardef@1ecf87corg.highwire.dtl.DTLVardef@adb3a0org.highwire.dtl.DTLVardef@1ebef93_HPS_FORMAT_FIGEXP M_FIG C_FIG