Down but Not Out: The Consequences of Pretangle Tau in the Locus Coeruleus

Abstract

Degeneration of locus coeruleus (LC) is an underappreciated hallmark of Alzheimer's disease (AD). The LC is the main source of norepinephrine (NE) in the forebrain, and its degeneration is highly correlated with cognitive impairment and amyloid-beta (Aβ) and tangle pathology. Hyperphosphorylated tau in the LC is among the first detectable AD-like neuropathology in the brain, and while the LC/NE system impacts multiple aspects of AD (e.g., cognition, neuropathology, and neuroinflammation), the functional consequences of hyperphosphorylated tau accrual on LC neurons are not known. Recent evidence suggests that LC neurons accumulate aberrant tau species for decades before frank LC cell body degeneration occurs in AD, suggesting that a therapeutic window exists. In this review, we combine the literature on how pathogenic tau affects forebrain neurons with the known properties and degeneration patterns of LC neurons to synthesize hypotheses on hyperphosphorylated tau-induced dysfunction of LC neurons and the prion-like spread of pretangle tau from the LC to the forebrain. We also propose novel experiments using both in vitro and in vivo models to address the many questions surrounding the impact of hyperphosphorylated tau on LC neurons in AD and its role in disease progression.

Higher rostral locus coeruleus integrity is associated with better memory performance in older adults

“…In animal models of Alzheimer's disease, LC lesions exacerbate both neural and behavioral decline 67 . In particular, in a mouse model of tauopathology, LC-ablated mice showed impaired memory and increased neuronal loss in the hippocampal formation compared with nonablated animals 68,81,82 . Further, in a rat model with both ß-amyloid and tau pathology, chemogenic activation of the LC rescued hippocampus-dependent behavior 79,83 .…”

“…Besides regulating healthy cognition 17,22,25,27,28 the LC subserves critical neuroprotective functions 34,67,68 . For instance, NE protects against neuroinflammation via the regulation of inflammatory gene expression and directly enhances clearance of aggregated ß-amyloid via activation of microglia 34,68 , two major threats to the aging brain 69 . This led Robertson and colleagues 70 to suggest that repeated activation of the LC-NE system (e.g., by exposure to novelty 33 ) helps maintain cognitive functionality in aging despite underlying neuropathological changes.…”

“…Recent analyses of large postmortem samples have indicated that the LC is among the earliest brain regions to show hyperphosphorylated tau, a hallmark of Alzheimer's disease (but see 76 for a different observation and 77 for a commentary), which accumulates in the nucleus linearly with the progression of the disease 8,12,78 . In tauopathies like Alzheimer's, misfolded tau proteins are thought to spread in a stereotypical, transcellular propagation pattern through neural networks 8,76 which may lead to tau pathology in prominent noradrenergic projection targets such as the medial temporal lobe 68 . Elevated tau levels are associated with more aggregated amyloid-ß, the second hallmark of Alzheimer's disease, and worse cognition 69 .…”

“…However, LC volume decreases by about 8% per Braak stage increment (i.e., a classification system that allows staging the progression of tau spread) followed by death of LC cells (from middle Braak stages on 12,79 ) that correlates with cognitive decline (for a review on the impact of hyperphosphorylated tau on LC, see 68 ). Of note, LC cell loss in Alzheimer's disease reaches profound levels (~50-80 % 67 ) and even surpasses neurodegeneration of the cholinergic nucleus basalis 80 .…”

The Norepinephrine Metabolite DOPEGAL Confers Locus Coeruleus Tau Vulnerability and Propagation via Asparagine Endopeptidase

“…Because hyperphosphorylated Tau can first be detected in the LC, and the LC sends dense projections to other vulnerable brain regions that display early Tau pathology (e.g., the transentorhinal cortex and hippocampus), some suggest that the LC might be one of the origins of Tau neuropathology in AD (4, 5). Although several theories have emerged to explain the selective vulnerability of LC neurons in AD, such as their unique anatomical, electrophysiological, morphological, and neurochemical characteristics (7, 16), the underlying molecular mechanisms have yet to be identified.…”