Functional Integrity of Synapses in the Central Nervous System of Cognitively Intact Individuals with High Alzheimer’s Disease Neuropathology Is Associated with Absence of Synaptic Tau Oligomers

Abstract

Background: Certain individuals, here referred to as Non-Demented with Alzheimer Neuropathology (NDAN), do not show overt neurodegeneration (N - ) and remain cognitively intact despite the presence of plaques (A+) and tangles (T+) that would normally be consistent with fully symptomatic Alzheimer’s disease (AD). Objective: The existence of NDAN (A + T +N - ) subjects suggests that the human brain utilizes intrinsic mechanisms that can naturally evade cognitive decline normally associated with the symptomatic stages of AD (A + T +N +). Deciphering the underlying mechanisms would prove relevant to develop complementing therapeutics to prevent progression of AD-related cognitive decline. Methods: Previously, we have reported that NDAN present with preserved neurogenesis and synaptic integrity paralleled by absence of amyloid oligomers at synapses. Using postmortem brain samples from age-matched control subjects, demented AD patients and NDAN individuals, we performed immunofluorescence, western blots, micro transplantation of synaptic membranes in Xenopus oocytes followed by twin electrode voltage clamp electrophysiology and fluorescence assisted single synaptosome-long term potentiation studies. Results: We report decreased tau oligomers at synapses in the brains of NDAN subjects. Furthermore, using novel approaches we report, for the first time, that such absence of tau oligomers at synapses is associated with synaptic functional integrity in NDAN subjects as compared to demented AD patients. Conclusion: Overall, these results give further credence to tau oligomers as primary actors of synaptic destruction underscoring cognitive demise in AD and support their targeting as a viable therapeutic strategy for AD and related tauopathies.

Cognitive and GABAergic protection by hAPPSw,Indand hTauVLWcoexpression: a model of Non-Demented with Alzheimer’s disease Neuropathology

“…The understanding of the mechanisms underlying cognitive neuroprotection in the presence of both Aβ and P-Tau pathological traits could have a major impact in the design of therapeutic strategies aimed at preventing cognitive decline in AD patients. A major factor proposed as responsible for this protection is the preservation of the synaptic machinery that normally degenerates in AD (Bjorklund et al, 2012;Singh et al, 2020;Zolochevska et al, 2018). In this regard, we propose that the simultaneous presence of Aβ and Tau with a specific phosphorylation pattern in J20/VLW mice may confer protection against the synaptotoxic effects of pathogenic oligomers, as seen in NDAN individuals, or may trigger a differential pattern of gene expression that protects synaptic structure and function.…”

“…Our results also point to the preservation of the GABAergic network as a critical factor underlying the recovery of cognitive and physiological deficits in J20/VLW mice. It is worth noting that the studies on NDAN subjects focus on glutamatergic synapses (Bjorklund et al, 2012;Singh et al, 2020;Zolochevska et al, 2018). Therefore, it would be of interest to analyze the state of GABAergic synapses in NDAN individuals to shed light on potential commonalities shared with J20/VLW mice.…”

“…Interestingly, several research groups have recently described the existence of individuals presenting the histopathological hallmarks of AD (namely Aβ plaques and P-Tau tangles) in the absence of cognitive impairment (Bjorklund et al, 2012;Briley et al, 2016;Erten-Lyons et al, 2009;Iacono et al, 2008;Singh et al, 2020;Zolochevska et al, 2018). This clinical entity, Non-Demented with AD Neuropathology (NDAN), is thought to have intrinsic mechanisms conferring neuroprotection against the classical degenerative AD processes.…”

“…This clinical entity, Non-Demented with AD Neuropathology (NDAN), is thought to have intrinsic mechanisms conferring neuroprotection against the classical degenerative AD processes. Several factors have been proposed as responsible for this protection, such as increased neurogenesis (Briley et al, 2016), increased hippocampal and total brain volume (which could indicate a larger cognitive reserve) (Erten-Lyons et al, 2009), neuronal and nuclear hypertrophy (Iacono et al, 2008), and preservation of the essential elements of the synaptic machinery that are dysfunctional in AD (Bjorklund et al, 2012;Singh et al, 2020). It has also been reported that NDAN individuals have a differential gene expression pattern at the postsynaptic density, which differs from that of AD and control subjects and could contribute to the mechanisms that confer synapse protection against AD pathology (Zolochevska et al, 2018).…”

Personalizing the Care and Treatment of Alzheimer’s Disease: An Overview

“… 35 This is in line with the findings of late amyloid accumulation in accelerated-senescence non-transgenic OXYS rats, 36 used as an animal AD model, and with the finding that functional integrity of synapses in the central nervous system (CNS) of cognitively intact individuals with high AD neuropathology is associated with the absence of synaptic tau oligomers. 37 Hence, in comparison to Braak stage-specific readouts, connectivity-based, personalized tau-PET readouts reduced the sample size of planned patient-centered simulated tau-targeting clinical trial interventions by approximately 40%. 38 …”