Effects of rising amyloidβ levels on hippocampal synaptic transmission, microglial response and cognition in APPSwe/PSEN1M146V transgenic mice

Dec 18, 2018EBioMedicine

Rising amyloid beta levels linked to changes in memory area signaling, immune cell response, and thinking in Alzheimer’s model mice

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Abstract

A notable increase in microglial numbers occurs in transgenic mice before the detection of amyloid plaques.

Microglial proliferation begins prior to the appearance of amyloid plaques and is associated with changes in synaptic transmission.
Long-term potentiation is enhanced before plaque formation but decreases with the initial emergence of plaques.
TASTPM mice exhibit altered non-cognitive behaviors despite showing no significant cognitive deficits, even with high plaque loads.
The relationship between microglial changes and synaptic alterations may be linked to low, non-toxic levels of amyloidβ rather than directly to plaque development.

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BACKGROUND: Progression of Alzheimer's disease is thought initially to depend on rising amyloidβ and its synaptic interactions. Transgenic mice (TASTPM; APP/PSEN1) show altered synaptic transmission, compatible with increased physiological function of amyloidβ, before plaques are detected. Recently, the importance of microglia has become apparent in the human disease. Similarly, TASTPM show a close association of plaque load with upregulated microglial genes. Swe M146V

METHODS: CA1 synaptic transmission and plasticity were investigated using in vitro electrophysiology. Microglial relationship to plaques was examined with immunohistochemistry. Behaviour was assessed with a forced-alternation T-maze, open field, light/dark box and elevated plus maze.

FINDINGS: The most striking finding is the increase in microglial numbers in TASTPM, which, like synaptic changes, begins before plaques are detected. Further increases and a reactive phenotype occur later, concurrent with development of larger plaques. Long-term potentiation is initially enhanced at pre-plaque stages but decrements with the initial appearance of plaques. Finally, despite altered plasticity, TASTPM have little cognitive deficit, even with a heavy plaque load, although they show altered non-cognitive behaviours.

INTERPRETATION: The pre-plaque synaptic changes and microglial proliferation are presumably related to low, non-toxic amyloidβ levels in the general neuropil and not directly associated with plaques. However, as plaques grow, microglia proliferate further, clustering around plaques and becoming phagocytic. Like in humans, even when plaque load is heavy, without development of neurofibrillary tangles and neurodegeneration, these alterations do not result in cognitive deficits. Behaviours are seen that could be consistent with pre-diagnosis changes in the human condition.

FUNDING: GlaxoSmithKline; BBSRC; UCL; ARUK; MRC.

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Effects of rising amyloidβ levels on hippocampal synaptic transmission, microglial response and cognition in APPSwe/PSEN1M146V transgenic mice

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