Human tau-overexpressing mice recapitulate brainstem involvement and neuropsychiatric features of early Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) poses an ever-increasing public health concern as the population ages, affecting more than 6 million Americans. AD patients present with mood and sleep changes in the prodromal stages that may be partly driven by loss of monoaminergic neurons in the brainstem, but a causal relationship has not been firmly established. This is due in part to a dearth of animal models that recapitulate early AD neuropathology and symptoms. The goal of the present study was to evaluate depressive and anxiety-like behaviors in a mouse model of AD that overexpresses human wild-type tau (htau) prior to the onset of cognitive impairments and assess these behavior changes in relationship to tau pathology, neuroinflammation, and monoaminergic dysregulation in the dorsal raphe nucleus (DRN) and locus coeruleus (LC). We observed depressive-like behaviors at 4 months in both sexes and hyperlocomotion in male htau mice. Deficits in social interaction persisted at 6 months and were accompanied by an increase in anxiety-like behavior in males. The behavioral changes at 4 months coincided with a lower density of serotonergic (5-HT) neurons, downregulation of 5-HT markers, reduced excitability of 5-HT neurons, and hyperphosphorylated tau in the DRN. Inflammatory markers were also upregulated in the DRN along with protein kinases and transglutaminase 2, which may promote tau phosphorylation and aggregation. Loss of 5-HT innervation to the entorhinal cortex and dentate gyrus of the hippocampus was also observed and may have contributed to depressive-like behaviors. There was also reduced expression of noradrenergic markers in the LC along with elevated phospho-tau expression, but this did not translate to a functional change in neuronal excitability. In total, these results suggest that tau pathology in brainstem monoaminergic nuclei and the resulting loss of serotonergic and/or noradrenergic drive may underpin depressive- and anxiety-like behaviors in the early stages of AD.

Tau pathology in the dorsal raphe may be a prodromal indicator of Alzheimer’s disease

“…In a recent study, a single-nucleotide polymorphism (SNP) in IL-12β linked to various types of cancer was also found to be associated with a heightened risk of late-onset AD [36]. Finally, we observed an increase in Fyn-related kinase (Frk) (t 8.82 =2.28, p< 0.05) which was elevated in the DRN of mice expressing wild-type human tau[37] and is known to contribute to the phosphorylation of tau.…”

A new insight into the role of CART peptide in serotonergic function and anxiety

“…Immunofluorescence was performed to localize CART and TPH2 neurons in the DRN of C57BL/6J as described previously [17,18]. 4-5 DRN sections were used across the rostral-caudal axis.…”

“…Social deficits were measured in the aCSF/CART microinjected mice in the social interaction test (SIT) as described previously [17]. Briefly, the test was conducted in a three-chambered Plexiglass with a small opening between the chambers.…”

Serotonergic dysfunction may mediate the relationship between alcohol consumption and Alzheimer’s disease

“…Preclinical animal models provide interim insight into this relationship. Transgenic mice expressing all isoforms of human tau develop depressive-like behaviors at 4 months of age, which coincides with the presence of NFTs and loss of neurons in the ventral rostral DR [ 94 ]. This particular region contains cortical-projecting 5-HT neurons that mediate stress-coping behaviors [ 58 ].…”