Frontotemporal lobar degeneration (FTLD) comprises a spectrum of dementia disorders with diverse pathologic underpinnings. In less than half of FTLD cases, designated FTLD-TAU, the abnormal inclusions consisting of hyperphosphorylated tau (Cairns et al. 2007a) are observed in various brain regions. In the past, FTLD cases without tau accumulation were designated FTLD-U because the only abnormal protein precipitate detected was ubiquitin (Cairns et al. 2007a). We now know that the vast majority of these cases contain abnormal precipitates of a phosphorylated and mislocalized form of tar DNA binding protein 43 (TDP-43), designated FTLD-TDP (Cairns et al. 2007a; Kwong et al. 2007).

TDP-43 is a 414 amino acid protein with two RNA recognition motifs which displays a strictly nuclear localization in normal brains (Chen-Plotkin et al. 2010; Lee et al. 2012), where it binds to a large number of RNA species (>6000), and thereby controls RNA transcription (pre-RNA processing), splicing and transport, and levels of microRNAs (Narayanan et al., 2013; Tollervey et al. 2011; Buratti et al. 2010). FTLD-TDP presents with mislocalization of TDP from the nucleus to the cytoplasm (Cairns et al. 2007b; Chen-Plotkin et al. 2010), an important step in TDP-43 aggregation and potential toxicity(Barmada et al. 2010). The mislocalized TDP-43 aggregates in intracytoplasmic inclusions, intranuclear inclusions and dystrophic neurites (Mackenzie and Neumann 2017; Mackenzie et al. 2007).

Cortical synaptic loss is an early and strong predictor of cognitive dysfunction and disease severity in a number of neurodegenerative dementias, particularly AD (Masliah et al. 1994, 2001; Terry et al. 1991; Scheff et al. 1990; DeKosky and Scheff 1990) and its prodromal stage amnestic mild cognitive impairment (aMCI) (Scheff et al. 2001, 2006, 2011). However, there is sparse information on the status of synapses in FTLD (Liu and Burn, 1996). Levels of the presynaptic protein synaptophysin display a decrease in the molecular layer of the dentate gyrus in Pick's disease, an FTLD tauopathy (Lippa 2004). Reductions in proteins associated with excitatory and inhibitory synapses have been reported in FTLD-Tau of progressive supranuclear palsy and in association with astrocytic plaques in corticobasal degeneration (Briel et al. 2021).

Many of the RNA targets of TDP-43 are involved in synaptic transmission and plasticity (Ling 2018), suggesting synaptic dysfunction as an early event contributing to cognitive deficits in FTLD-TDP. This possibility is strengthened by the role of TDP-43 in genesis of dendritic spines (Majumder et al. 2012), which are dynamic sites of excitatory synapses in the brain. A study of tau-negative FTLD cases (presumably mostly FTLD-TDP), found significant loss of the synaptic protein SNAP-25 in the prefrontal cortex (Connelly et al. 2011). Whole transcriptome array of frontal cortex of FTLD-TDP showed changes in transcripts related to synapses (Andres-Benito et al. 2018), however the fate of the respective proteins is unknown. Transgenic mice overexpressing mutated or wild-type human TDP show loss of synaptic proteins synaptophysin and synapsin-1 (Heyburn et al. 2016; Medina et al. 2014). In the present report, we provide information regarding the status of the presynaptic protein synaptophysin, the postsynaptic protein postsynaptic density-95 (PSD-95), and the dendritic spine protein spinophilin in the middle frontal gyrus (MFG), posterior aspects of the middle temporal gyrus (MTG), and primary visual cortex of participants with the behavioral variant of FTLD-TDP.

Microglia play a major role in synaptic pruning during neural development and studies utilizing microglia ablation indicate that they also prune synapses in the adult brain(Spangenberg and Green 2017; Hong et al. 2016). Importantly, abnormal microglia synaptic pruning may participate in the synaptic loss seen in AD. In several animal models of AD, microglia ablation resulted in increased numbers of synapses and improved memory (Hong et al. 2016; Spangenberg and Green 2017). Thus, the process of microglia mediated developmental synaptic pruning may be abnormally enhanced in neurodegenerative disorders and contribute to synaptic loss. In the present report we investigated microglia phagocytosis of synaptic proteins in the MFG as a potential surrogate marker of synaptic pruning in FTLD-TDP.