Pathological changes induced by Alzheimer’s brain inoculation in amyloid-beta plaque-bearing mice

Abstract

Alzheimer's disease (AD) is characterized by intracerebral accumulations of extracellular amyloid-β (Aβ) plaques and intracellular tau pathology that spread in the brain. Three types of tau lesions occur in the form of neuropil threads, neurofibrillary tangles, and neuritic plaques i.e. tau aggregates within neurites surrounding Aβ deposits. The cascade of events linking these lesions and synaptic or memory impairments are still debated. Intracerebral infusion of human AD brain extracts in Aβ 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 present study, human AD brain extracts (ADbe) and control-brain extracts (Ctrlbe) were infused into the hippocampus of Aβ plaque-bearing APPswe/PS1dE9 mice. Memory, synaptic density, as well as Aβ 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 produced the following effects: (i) memory deficit; (ii) increased Aβ plaque deposition in proximity to the inoculation site; (iii) tau pathology induction; (iv) appearance of neuropil threads and neurofibrillary tangles next to the inoculation site with a spreading to connected regions. Neuritic plaque pathology was detected in both ADbe- and Ctrlbe-inoculated animals but ADbe inoculation increased the severity close to and at distance of the inoculation site. (v) Finally, ADbe inoculation reduced synaptic density in the vicinity 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 to other tau lesions or Aβ lesions, suggesting that neuritic plaques are a culprit for synaptic loss. Synaptic density was also associated with microglial load. Graphical abstract

Protein Interactome of Amyloid-β as a Therapeutic Target

“…Notably, tau phosphorylation is an ordinary event in cell physiology [ 53 , 54 ], and eight possible phosphorylation sites have been discovered on all six isoforms of tau [ 55 , 56 ]. The mechanisms of Aβ’s effect on tau hyperphosphorylation are not yet clear, despite the fact that there is much evidence of the two polypeptides’ coaggregation in the brains of AD patients [ 57 , 58 ]. In a recent report, the effect of Aβ on the kinases phosphorylating tau was evidenced [ 59 ], while earlier data suggest the possibility of targeting by Aβ available tau phosphorylation sites [ 60 ] ( Figure 2 A).…”

Long term worsening of Alzheimer pathology and clinical outcome by a single inoculation of mutated beta-amyloid seeds

“…As Aβ is known to induce synaptic de cits either ex vivo or in transgenic mouse models [24][25][26], it seems reasonable to consider that the increased Aβ plaque deposition and reorganization of oligomeric patterns induced by Aβ osa was, at least in part, responsible for the cognitive and synaptic impairments detected in Aβ osa -inoculated APP swe /PS1 dE9 mice. As the tau pathology within neuritic plaques was correlated with synaptic impairments in APP swe /PS1 dE9 mice [12], we investigated tau pathology and found that different Aβ seeds did not modulate tau lesion occurrence. This rules out the role of tau pathology on the synaptic changes observed in the Aβ osa -inoculated animals.…”

“…In particular, they exhibit preferred conformational states that allow higher hydrophobicity resulting in faster oligomerization [17]. The long-term effect of a single intra-hippocampal inoculation of each Aβ osa seed was evaluated four months post inoculation in transgenic mice (APP swe /PS1 dE9 ) overexpressing Aβ 1−42 peptide and presenting Aβ plaques and neuritic plaques [12]. We provide evidence that exposure to Aβ osa induces cognitive and functional impairments, including reduced hippocampal connectivity compared to mice inoculated with non-mutated Aβ 1−42 peptide (Aβ wt ).…”

“…In addition to Aβ lesions, the inoculation of AD-brain extracts can induce long-term cognitive alterations as well as synaptic impairments in rodents [12] or primates [8,13]. As inoculation of AD-brain extracts can induce both Aβ and tau pathologies [12], it is di cult to dissociate the role of Aβ or tau on cognitive or synaptic impairments induced by this inoculation [12]. Thus, inoculation of Aβ oligomers was proposed to evaluate the impact of Aβ seeds on brain function.…”

Microglia and Alzheimer’s Disease

“…Recent genomic and transcriptome studies have supported the idea that pathways associated to microglia are essential for the risk and pathogenesis of AD [ 10 ]. It’s interesting to note that recent research has shown that microglia accumulate close to amyloid-beta plaques in the AD brain and increase disease severity [ 28 , 29 , 30 ]. Therefore, the topic of this review is to offer an overview on microglia involvement in neuroinflammation and AD pathology.…”