Pretangle pathology within cholinergic nucleus basalis neurons coincides with neurotrophic and neurotransmitter receptor gene dysregulation during the progression of Alzheimer's disease

Abstract

Cholinergic basal forebrain neurons of the nucleus basalis of Meynert (nbM) regulate attentional and memory function and are exquisitely prone to tau pathology and neurofibrillary tangle (NFT) formation during the progression of Alzheimer’s disease (AD). nbM neurons require the neurotrophin nerve growth factor (NGF), its cognate receptor TrkA, and the pan-neurotrophin receptor p75NTR for their maintenance and survival. Additionally, nbM neuronal activity and cholinergic tone are regulated by the expression of nicotinic (nAChR) and muscarinic (mAChR) acetylcholine receptors as well as receptors modulating glutamatergic and catecholaminergic afferent signaling. To date, the molecular and cellular relationships between the evolution of tau pathology and nbM neuronal survival remain unknown. To address this knowledge gap, we profiled cholinotrophic pathway genes within nbM neurons immunostained for pS422, a pretangle phosphorylation event preceding tau C-terminal truncation at D421, or dual-labeled for pS422 and TauC3, a later stage tau neo-epitope revealed by this same C-terminal truncation event, via single-population custom microarray analysis. nbM neurons were obtained from postmortem tissues from subjects who died with an antemortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or mild/moderate AD. Quantitative analysis revealed significant downregulation of mRNAs encoding TrkA as well as TrkB, TrkC, and the Trk-mediated downstream pro-survival kinase Akt in pS422+ compared to unlabeled, pS422-negative nbM neurons. In addition, pS422+ neurons displayed a downregulation of transcripts encoding NMDA receptor subunit 2B, metabotropic glutamate receptor 2, D2 dopamine receptor, and β1 adrenoceptor. By contrast, transcripts encoding p75NTR were downregulated in dual-labeled pS422+/TauC3+ neurons. Appearance of the TauC3 epitope was also associated with an upregulation of the α7 nAChR subunit and differential downregulation of the β2 nAChR subunit. Notably, we found that gene expression patterns for each cell phenotype did not differ with clinical diagnosis. However, linear regression revealed that global cognition and Braak stage were predictors of select transcript changes within both unlabeled and pS422+/TauC3™ neurons. Taken together, these cell phenotype-specific gene expression profiling data suggest that dysregulation of neurotrophic and neurotransmitter signaling is an early pathogenic mechanism associated with NFT formation in vulnerable nbM neurons and cognitive decline in AD, which may be amenable to therapeutic intervention early in the disease process.

Synapsin-caveolin-1 Mitigates Cognitive Deficits and Neurodegeneration in PSAPP Mice

“…2A). Co-staining of the dendritic marker MAP2 with Cav-1 showed decreased MAP2 expression in the hippocampal CA1 subfield and cortex in PSAPP-SynRFP, similar to that observed in postmortem human brains of patients diagnosed with CTE, tauopathy, and AD [17,18]. In contrast, PSAPP-SynCav1 mice displayed increased hippocampal (Fig.…”

“…One such gene therapy candidate is caveolin-1 (Cav-1), a MLR scaffolding protein that organizes NTRs (Trk) and neurotransmitter receptor signaling complexes in MLRs [12][13][14]. Both pre-clinical and clinical findings revealed that Cav-1 and Cav-1 associated signaling complexes (NTRs and neurotransmitter receptors) were decreased in degenerating neurons in AD, chronic traumatic encephalopathy (CTE), and amyotrophic lateral sclerosis (ALS) [15][16][17][18]. In contrast, we previously showed that neuron-targeted Cav-1 over-expression (i.e., synapsin-promoted Cav-1 or SynCav1) augmented agonist-mediated synaptic signaling (e.g., NTRs, neurotransmitter receptors) and dendritic arborization in vitro [12], preserved MLR-localized TrkB and extended life span in ALS mice [19], suggesting that alterations in Cav-1 expression affects pro-survival signaling and neuroprotection in neurodegenerative conditions .…”

Tau and Axonal Transport Misregulation in Tauopathies

“…Expression of another FTDP-17 mutant tau, A152T, in C. elegans neurons led to abnormal localization of synaptic vesicles that may be due to minor disruptions in aFAT and rFAT independent of any tau aggregation or changes to microtubule binding [14,73]. These studies do not identify a specific signaling pathway, but the conclusions may be similar to observed impairment of aFAT and rFAT by tau filaments phosphorylated at S422 [93], a disease-specific phosphorylation event that occurs early in pre-tangles and robustly labels neuropil threads in areas of the brain involved in memory and cognition [32,94]. Such observations suggest that certain modifications in tau may expose PAD and other domain(s) that in turn activate alternative signaling pathways.…”

Expression profiling of precuneus layer III cathepsin D‐immunopositive pyramidal neurons in mild cognitive impairment and Alzheimer's disease: Evidence for neuronal signaling vulnerability

“…Another consideration is that this investigation examined PreC CatDimmunopositive neurons irrespective of NFT status. Since we did not differentiate NFT-positive or negative neurons, as done in prior studies (Tiernan et al, 2016(Tiernan et al, , 2018, we were unable to attribute the effect of tau pathology on specific expression profiles during the progression of dementia. This neuronal distinction will be investigated upon access Volunteer subjects may introduce bias by decreasing pathology but this, in part, is mitigated by the high follow-up and autopsy rates of the RROS cohort (Bennett et al, 2005).…”