A novel brainstem pathway to the circadian system links Tau neurofibrillary pathology to sundowning-related circadian dysfunction and associated sex differences in the TAPP mouse model of Alzheimer’s disease
Authors: Warfield Andrew , Gupta Pooja , Ruhmann Madison , Jeffs Quiana , Guidone Genevieve , Rhymes Hannah , Thompson McKenzi , Todd William 
Published: December 2022

Abstract
Patients with Alzheimer’s disease (AD) exhibit a progressive disruption of entrained circadian rhythms that first appears long before cognitive symptoms develop. Additionally, work combining analyses of actigraphy and hypothalamic tissue from AD patients suggests that an input to the circadian system may underlie such dysfunction, rather than the presence of pathology and neurodegeneration in the master circadian pacemaker (the suprachiasmatic nucleus, SCN), itself. Here we examined the accumulation of Tau and beta-amyloid pathology and its association with circadian dysfunction in the TAPP (also called APPSwe-Tau) mouse model. We particularly focused on whether sex differences in the development of such pathology influence the onset of circadian dysfunction and investigated which neural areas affected by such pathology also project to the circadian system. We show that TAPP mice, which express mutant human Tau and amyloid precursor protein mutations, exhibit phase delays in rhythms of both body temperature (Tb) and locomotor activity (LMA), revealed by later bathyphases (troughs) and later acrophases (peaks) of these rhythms, which are commonly seen in AD patients. TAPP mice notably showed increases in Tb and LMA around the transition between their active and resting phases (late dark to early light period transition). This is temporally consistent with when AD patients frequently exhibit sundowning, which is characterized by wandering, agitation, and aggression in the late afternoon and early evening. Indeed, sundowning has also been shown to be strongly associated with the reported phase delay in AD patients. We showed these disruptions of entrained rhythms coincide with the development of intracellular neurofibrillary tangles expressing hyperphosphorylated Tau (pTau). Interestingly, we found that both circadian dysfunction and associated pathology develop earlier in female TAPP mice than in males. Additionally, the presence of LPB pTau and circadian dysfunction in older TAPP males is associated with an increase in behavioral aggression just before the active-resting phase transition, which is temporally analogous to when AD patients show sundowning-related aggression. While AD pathology can be detected in numerous brain areas in TAPP mice, we find that the appearance of such physiological and behavioral rhythm disturbances is most consistently associated with the expression of pTau in the lateral parabrachial nucleus (LPB). Using retrograde tracing combined with in situ hybridization, and genetically targeted anterograde tracing, we further show that dynorphin-expressing LPB neurons (LPBdyn) project to the circadian system and are particularly affected by pTau in TAPP mice. Finally, we demonstrated that genetically targeted ablation of LPBdyn neurons resulted in increases in body temperature that partially recapitulated the phenotype of TAPP mice. These findings suggest that a loss of LPBdyn cells is an important part of AD pathogenesis related to circadian dysfunction and sundowning-related disturbances. Importantly, the LPB region has been shown to exhibit pTau and neurodegeneration in AD patients. This study is the first to demonstrate a specific subset of LPB neurons that projects to the circadian system and is associated with AD-related circadian dysfunction.