Chronic γ-secretase inhibition reduces amyloid plaque-associated instability of pre- and postsynaptic structures

Abstract

The loss of synapses is a strong histological correlate of the cognitive decline in Alzheimer's disease (AD). Amyloid β−peptide (Aβ), a cleavage product of the amyloid precursor protein (APP), exerts detrimental effects on synapses, a process thought to be causally related to the cognitive deficits in AD. Here, we used in vivo two-photon microscopy to characterize the dynamics of axonal boutons and dendritic spines in APP/Presenilin 1 (APPswe/PS1L166P)–green fluorescent protein (GFP) transgenic mice. Time-lapse imaging over 4 weeks revealed a pronounced, concerted instability of pre- and postsynaptic structures within the vicinity of amyloid plaques. Treatment with a novel sulfonamide-type γ-secretase inhibitor (GSI) attenuated the formation and growth of new plaques and, most importantly, led to a normalization of the enhanced dynamics of synaptic structures close to plaques. GSI treatment did neither affect spines and boutons distant from plaques in amyloid precursor protein/presenilin 1-GFP (APPPS1-GFP) nor those in GFP-control mice, suggesting no obvious neuropathological side effects of the drug.

Anti-inflammatory treatment with FTY720 starting after onset of symptoms reverses synaptic and memory deficits in an AD mouse model

“…The spine deficits observed at this age in untreated AD mice strongly depended on the proximity of CA1 pyramidal cell dendrites to the closest Aβ plaque. This observation was consistent with the previously reported spine instability recorded in vivo in the neocortex of 3-4 months old animals of the same APP/PS1 mouse model as used in our study, which was also more pronounced in the vicinity of Aβ plaques (Liebscher et al, 2014). These results suggest that increased instability of spines in living tissue (Liebscher et al, 2014) correlates with net spine loss that can be detected with Golgi-Cox staining (our study).…”

Long-term dynamics of aberrant neuronal activity in Alzheimer’s disease

“…Interestingly, recent findings suggest that PV interneurons are also involved in facilitating 'baseline' synchrony of neural circuits during quiescent states and that their optogenetic silencing yields a drop in network synchrony both during visual stimulation as well as during spontaneous activity 39 . The observed increase in correlated spontaneous activity in our data thus might result from aberrant correlated synaptic excitatory inputs, which could result from structural remodelling known to accompany for instance amyloid plaque pathology 12,40 . In line with this idea are also findings reporting increased local connectivity and synchronization in AD, while inter-regional connectivity was strongly decreased 41,42 .…”

“…Effect of amyloid plaque proximity A plaques are a hallmark of AD pathology, and even though their pathogenic relevance is currently debated 28,29 , the local plaque environment is associated with a number of pathological features, such as dystrophic neurites, synapse loss and instability 12 , reactive microglia and astrocytes and hyperactive neurons 1 . We thus asked whether neurons close to plaques would change their activity more vigorously or frequently than neurons further away from plaques.…”

“…A has been shown to bind to several surface molecules of synapses 7,8 , particularly to postsynaptic elements of excitatory synapses 9 . Moreover, A causes synaptic instability, a 'shrinkage of spines' and synaptic loss, which are accompanied by a reduction of LTP and increased LTD both in vitro and in vivo [10][11][12] . Counterintuitively, A can trigger an 'aberrant' increase in neuronal activity both acutely as well as under chronic conditions, such as in transgenic mouse models, which has been suggested to result from the activation of NMDA and AMPA receptors 1,[13][14][15][16] through increased glutamate release probability 17 or blockage of glutamate uptake [18][19][20] .…”

[3H]‐L685,458 Binding Sites are Abundant in Multiple Peripheral Organs in Rats: Implications for Safety Assessment of Putative γ‐Secretase Targeting Drugs

“…Toxicological implications for putative c-secretase targeting drugs. c-Secretase inhibitory compounds have and are being developed on the pipeline as potential anti-Ab and anticancer drugs [7,26,[42][43][44][45][46]. High-dose or long-time application of these drugs might be needed for these disease conditions, yet scanty data are available for chronic toxicity of the compounds.…”