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

Abstract

BackgroundProgression of Alzheimer's disease is thought initially to depend on rising amyloidβ and its synaptic interactions. Transgenic mice (TASTPM; APPSwe/PSEN1M146V) 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.MethodsCA1 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.FindingsThe 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.InterpretationThe 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.FundingGlaxoSmithKline; BBSRC; UCL; ARUK; MRC.

A Unifying Hypothesis for Alzheimer’s Disease: From Plaques to Neurodegeneration

“…1A & 2A). In addition, long-term potentiation is increased at these earliest stages in transgenic mice, but becomes impaired as levels continue to rise [16]. These findings are consistent with the proposed physiological functions of amyloidβ [7], and with other previous reports of the positive effects of low picomolar levels of amyloidβ on synaptic transmission as opposed to the toxic effects seen at higher concentrations [11].…”

“…As outlined above however, it is important to note that even when the plaque load appears to be extensive, particularly across the hippocampus and cortex, the percent of brain tissue directly in contact with the plaques and hence affected by this toxic area remains very low. For example in brain sections from a transgenic mouse with hundreds of plaques detectable/mm 2 , the plaque coverage of hippocampal area is only ~10% and much lower at earlier stages [16]. Consistent with this, in humans, the total proportion of the neuropil covered by plaques, even in advanced stages of Alzheimer's disease, is generally only around 5-10%, on postmortem analysis [27].…”

Improving Mouse Models for Dementia. Are All the Effects in Tau Mouse Models Due to Overexpression?

“…Interestingly, transgenic models expressing only single mutations in APP or PSEN1 (as occurs in familial Alzheimer's disease) generally do not feature plaques or not until very late in the life of the mouse. For example, a transgenic mouse that only expresses APP with the Swedish mutation starts to develop plaques at ∼18 mo of age, although mice with the same mutation combined with a PSEN1 M146V mouse start to deposit plaques at ∼4 mo of age (Matarin et al 2015;Medawar et al 2018). The PSEN1 mutation alone does not result in plaques within the lifetime of the mouse (Matarin et al 2015;Medawar et al 2018).…”

“…For example, a transgenic mouse that only expresses APP with the Swedish mutation starts to develop plaques at ∼18 mo of age, although mice with the same mutation combined with a PSEN1 M146V mouse start to deposit plaques at ∼4 mo of age (Matarin et al 2015;Medawar et al 2018). The PSEN1 mutation alone does not result in plaques within the lifetime of the mouse (Matarin et al 2015;Medawar et al 2018). Consequently, to see plaques more rapidly, many models overexpress APP and either PSEN1 or PSEN2, with both transgenes harboring familial mutations.…”

“…Briefly, although the effect of the mutations on pathology have not been questioned, the effects on synaptic transmission, both early, as pathology is first developing (Cummings et al 2015), and at later stages (Busche and Konnerth 2015;Medawar et al 2018), could be highly influenced by overexpression of other APP metabolites. The earliest effect of rising Aβ is an increase in glutamate release probability.…”