3/5/2023 0 Comments Long road to ruinThus, dysregulated hyperactivity of a subset of LC neurons (e.g. LC neurons are also electrically coupled via gap junctions, which drives their synchronous firing. Interestingly, mitochondrial stress is elevated in the LC neurons of mice lacking DJ-1, a protein implicated in heritable early onset forms of PD. The potential for LC hyperactivity in early stage disease would exacerbate Ca2 + influx and mitochondrial toxicity. Pacemaker activity is maintained by Ca2 + channels, and Ca2 + that enters the cell can be shuttled to mitochondria, further promoting oxidative stress. Thus, the bioenergetic needs of these cells are high and rely on mitochondrial oxidative phosphorylation, which can produce significant levels of oxidative stress over time. LC neurons display nearly constant “pacemaker” activity that is increased by stress, with acute phasic bursting patterns in response to salient sensory stimuli superimposed on the tonic firing. It is worth noting that human LC neurons contain neuromelanin, while all other non-primate animals examined (including rodents, which are most commonly used as model organisms to study AD and PD) do not, and humans are the only species that develop sporadic AD and PD. Neuromelanin may initially protect LC neurons by chelating damaging agents, but eventually aggravate neurodegeneration by releasing the toxins later in life. LC neurons also synthesize neuromelanin, a granular pigment that binds iron and other heavy metals, as well as chemical toxicants and even α-synuclein. LC hyperactivity, which may occur prior to degeneration in AD and PD as proposed in this review, would increase NE turnover and thus DOPEGAL production, leading to further cellular stress. 3,4-dihydroxyphenylglycolaldehyde DOPEGAL) by monoamine oxidase (MAO), which can then cause damage to proteins, lipids, and nucleotides. Cytoplasmic NE can autoxidize or be converted to chemically reactive and toxic metabolites (e.g. NE is normally sequestered inside synaptic vesicles by the vesicular monoamine transporter 2 (VMAT2), but after synaptic release, it is taken up into the cytoplasm by the NE transporter (NET). NE, the primary neurotransmitter of LC neurons, is itself a risk factor. Although it is not yet clear exactly why noradrenergic neuropathology, dysfunction, and degeneration is initiated so early in AD and PD compared to other nuclei, LC neurons have several anatomical, morphological, and neurochemical characteristics that likely contribute to their vulnerability ( Box 1). Importantly, normal aging does not affect the LC, indicating that the degeneration is directly related to disease progression. These LC pathologies often precede the primary symptoms of each disorder (dementia in AD, motor dysfunction in PD), suggesting that LC loss may contribute to disease initiation, progression, and severity rather than merely representing collateral damage in a dying brain. Likewise, α-synuclein pathology appears in LC neurons before infiltrating the substantia nigra pars compacta, the canonical midbrain dopaminergic nucleus that controls motor function. For example, hyperphosphorylated tau, a “pretangle” form of the protein that is prone to aggregation, can be detected in the LC before anywhere else in the brain, sometimes during the first few decades of life. Second, evidence from postmortem studies indicates that some of the primary AD (tau) and PD (α-synuclein) pathologies appear very early in the LC. First, we and others have shown that LC lesions exacerbate AD- and PD-like neuropathology and cognitive/behavioral deficits in animal models. The neurodegeneration field has recently taken notice of the LC for two reasons. Although nearly ubiquitous and profound (~50–80%), it was largely ignored in favor of other neurotransmitter systems/nuclei, even though the extent of LC/NE degeneration surpasses even nucleus basalis/acetylcholine loss in AD and dopamine (DA)/substantia nigra loss in PD. LC cell loss was first described in AD and PD more than 30 years ago. Given the importance of the LC for the regulation of attention, arousal, and mood, a potential role for LC degeneration has been suggested for certain neuropsychiatric abnormalities that are common in both AD and PD, such as anxiety, depression, and sleep disorders. An underappreciated hallmark of both diseases is the degeneration of the brainstem locus coeruleus (LC), the major norepinephrine (NE)-producing nucleus in the brain. While their primary symptoms are distinct (memory loss in AD, motor symptoms in PD), both are characterized by protein aggregates (β-amyloid plaques and tau neurofibrillary tangles in AD, α-synuclein Lewy bodies in PD), and they share co-morbid symptoms such as depression, anxiety, sleep abnormalities, and cognitive impairment. Locus Coeruleus Degeneration in Alzheimer’s disease and Parkinson’s diseaseĪlzheimer disease (AD) and Parkinson’s disease (PD) are the two most prevalent neurodegenerative diseases.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |