Project Summary/Abstract
Alzheimer's disease and related dementias are associated with progressive disruption of circadian rhythms.
One particular feature of such circadian dysfunction in patients with AD and related dementias is “sundowning
syndrome”, a poorly understood clinical phenomenon characterized by agitation, aggression, and delirium
during the early evening hours. Such symptoms have a major impact on the quality of life for both the patient
and their caregivers and often lead to the decision to seek institutionalization. The neurobiology of sundowning
remains unknown, however the temporal periodicity of sundowning symptoms suggests a possible disturbance
in the master circadian clock, the suprachiasmatic nucleus (SCN) of the hypothalamus, or in the pathways by
which the SCN modulates particular rhythms. Rhythms of sleep-wake and LMA are known to be regulated by
the SCN via a pathway through its major postsynaptic target, the subparaventricular zone (SPZ), to the
dorsomedial hypothalamus (DMH). Additionally, I recently demonstrated that the propensity for behavioral
aggression also follows a daily rhythm that is regulated by the SCN, via an additional pathway through the
SPZ, to the ventromedial hypothalamus (VMH). Importantly, disrupting this SCN¿SPZ¿VMH pathway led to
increased aggression during the early resting phase (the light period for nocturnal mice), which is temporally
analogous to when AD and dementia patients who experience sundowning display increased agitation and
aggression. This suggests that the function of certain structures within this circuit may be compromised in AD
and dementia, and that this pathway may be a promising therapeutic target for treating circadian dysfunction
and aggression in patients who display sundowning. To test this novel hypothesis, I began examining circadian
rhythms in the TAPP mouse model, which develops amyloid-beta (a-beta) plaques and tau neurofibrillary
tangles (both hallmarks of AD neuropathology), and my preliminary results suggest that these mice exhibit
increased early resting period aggression and blunted active period LMA at ages shortly after they first develop
AD-related neuropathology. In this proposal, I will examine tissue from these mice for AD-related
neuropathological markers in the SCN, the SPZ and its output targets the VMH and the DMH. It has been
hypothesized that circadian dysfunction associated with sundowning results instead from AD-related
disturbances to areas that provide input to the circadian system, such as serotoninergic and cholinergic
pathways, and I will also examine neuropathology in such areas. Additionally, I will also examine activated
astrocytes in all of these circadian pathways, as such glial responses have been show to be associated with
neuroinflammation and neurodegeneration in AD, and normal astrocyte functioning is known to be critical to
the circadian system's ability to maintain proper time-keeping. Finally, I seek to determine the effects of
manipulating SPZ activity (using chemogenetic activation) on the increased daytime aggression and blunted
circadian sleep-wake rhythms in TAPP mice, and on the patterns of neuropathology and astrocyte responses.
