Cognitive, synaptic and neuropathological changes in Alzheimer’s brain-inoculated mice

Abstract

Alzheimer’s disease is characterized by lesions including extracellular amyloid-β plaques, intracellular tau accumulations, activated microglia around amyloid plaques and synaptic alterations that lead to cognitive impairments. Tau lesions occur in the form of tau-positive aggregates surrounding amyloid-β deposits leading to neuritic plaques, neuropil threads, and neurofibrillary tangles. The interactions between these lesions and their contribution to cognitive impairments are still debated.

In this study, through the intrahippocampal inoculation of human Alzheimer-brain extracts into an amyloid-β plaque-bearing mouse model, we induced amyloid plaques, Alzheimer-like tau- positive neuritic plaques, neuropil threads and neurofibrillary tangles that spread through the brain, microgliosis as well as synaptic and cognitive impairments in some animals.

Neuritic plaques, but not other tau-positive lesions, were detected in both non-inoculated and control-brain-inoculated amyloid-β plaque-bearing mice. Alzheimer-brain extracts inoculation further increased tau pathology within neuritic plaques. As opposed to the control-brain extract, Alzheimer-brain extracts induced neuropil threads and neurofibrillary tangles next to the inoculation site. These lesions also spread to connected brain regions such as the perirhinal/entorhinal cortex.

Different levels of synaptic loss and cognitive impairments were induced by inoculating two types of Alzheimer-brain extracts originating from slowly (clAD) or rapidly evolving forms of Alzheimer’s disease (rpAD), although no difference in amyloid-β deposition, tau pathology and microgliosis was identified between clAD- and rpAD-inoculated animals.

A complementary analysis investigated relationships between synaptic or cognitive impairments and Alzheimer pathology. Synaptic defects were associated with the severity of tau lesions and with lower microglial load. Lower cognitive scores correlated with synaptic defects as well as with amyloid and tau pathologies in the hippocampus, and with tau lesions in the perirhinal/entorhinal cortex.

Taken together, this study shows that amyloid-β deposits are sufficient to induce tau pathology within neuritic plaques in Aβ plaque–bearing mice that do not overexpress tau. Alzheimer-brain extract inoculation however increases tau pathology within neuritic plaques, and induces neuropil threads and neurofibrillary tangles that spread in the brain. Inoculation of different human Alzheimer-brain extracts leads to different levels of synaptic loss and cognitive impairments. Synaptic loss and cognitive impairments are associated with multiple factors such as the severity of tau lesions and lower microglial activity, as well as amyloid deposition for cognitive changes. These results highlight that microglial activity may protect against synaptic loss.