Search for: All records

Alzheimer’s disease cortical tau pathology initiates in the layer II cell clusters of entorhinal cortex, but it is not known why these specific neurons are so vulnerable. Aging macaques exhibit the same qualitative pattern of tau pathology as humans, including initial pathology in layer II entorhinal cortex clusters, and thus can inform etiological factors driving selective vulnerability. Macaque data have already shown that susceptible neurons in dorsolateral prefrontal cortex express a “signature of flexibility” near glutamate synapses on spines, where cAMP-PKA magnification of calcium signaling opens nearby potassium and hyperpolarization-activated cyclic nucleotide-gated channels to dynamically alter synapse strength. This process is regulated by PDE4A/D, mGluR3, and calbindin, to prevent toxic calcium actions; regulatory actions that are lost with age/inflammation, leading to tau phosphorylation. The current study examined whether a similar “signature of flexibility” expresses in layer II entorhinal cortex, investigating the localization of PDE4D, mGluR3, and HCN1 channels. Results showed a similar pattern to dorsolateral prefrontal cortex, with PDE4D and mGluR3 positioned to regulate internal calcium release near glutamate synapses, and HCN1 channels concentrated on spines. As layer II entorhinal cortex stellate cells do not express calbindin, even when young, they may be particularly vulnerable to magnified calcium actions and ensuing tau pathology.

 

Abstract The primate prefrontal cortex (PFC) subserves our highest order cognitive operations, and yet is tremendously dependent on a precise neurochemical environment for proper functioning. Depletion of noradrenaline and dopamine, or of acetylcholine from the dorsolateral PFC (dlPFC), is as devastating as removing the cortex itself, and serotonergic influences are also critical to proper functioning of the orbital and medial PFC. Most neuromodulators have a narrow inverted U dose response, which coordinates arousal state with cognitive state, and contributes to cognitive deficits with fatigue or uncontrollable stress. Studies in monkeys have revealed the molecular signaling mechanisms that govern the generation and modulation of mental representations by the dlPFC, allowing dynamic regulation of network strength, a process that requires tight regulation to prevent toxic actions, e.g., as occurs with advanced age. Brain imaging studies in humans have observed drug and genotype influences on a range of cognitive tasks and on PFC circuit functional connectivity, e.g., showing that catecholamines stabilize representations in a baseline-dependent manner. Research in monkeys has already led to new treatments for cognitive disorders in humans, encouraging future research in this important field. 

Abstract Neurons in the association cortices are particularly vulnerable in cognitive disorders such as schizophrenia and Alzheimer’s disease, while those in primary visual cortex remain relatively resilient. This review proposes that the special molecular mechanisms needed for higher cognitive operations confer vulnerability to dysfunction, atrophy, and neurodegeneration when regulation is lost due to genetic and/or environmental insults. Accumulating data suggest that higher cortical circuits rely on magnified levels of calcium (from NMDAR, calcium channels, and/or internal release from the smooth endoplasmic reticulum) near the postsynaptic density to promote the persistent firing needed to maintain, manipulate, and store information without “bottom-up” sensory stimulation. For example, dendritic spines in the primate dorsolateral prefrontal cortex (dlPFC) express the molecular machinery for feedforward, cAMP–PKA–calcium signaling. PKA can drive internal calcium release and promote calcium flow through NMDAR and calcium channels, while in turn, calcium activates adenylyl cyclases to produce more cAMP–PKA signaling. Excessive levels of cAMP–calcium signaling can have a number of detrimental effects: for example, opening nearby K + channels to weaken synaptic efficacy and reduce neuronal firing, and over a longer timeframe, driving calcium overload of mitochondria to induce inflammation and dendritic atrophy. Thus, calcium–cAMP signaling must be tightly regulated, e.g., by agents that catabolize cAMP or inhibit its production (PDE4, mGluR3), and by proteins that bind calcium in the cytosol (calbindin). Many genetic or inflammatory insults early in life weaken the regulation of calcium–cAMP signaling and are associated with increased risk of schizophrenia (e.g., GRM3 ). Age-related loss of regulatory proteins which result in elevated calcium–cAMP signaling over a long lifespan can additionally drive tau phosphorylation, amyloid pathology, and neurodegeneration, especially when protective calcium binding proteins are lost from the cytosol. Thus, the “genie” we need for our remarkable cognitive abilities may make us vulnerable to cognitive disorders when we lose essential regulation. 

Chronic exposure to uncontrollable stress causes loss of spines and dendrites in the prefrontal cortex (PFC), a recently evolved brain region that provides top-down regulation of thought, action, and emotion. PFC neurons generate top-down goals through recurrent excitatory connections on spines. This persistent firing is the foundation for higher cognition, including working memory, and abstract thought. However, exposure to acute uncontrollable stress drives high levels of catecholamine release in the PFC, which activates feedforward calcium-cAMP signaling pathways to open nearby potassium channels, rapidly weakening synaptic connectivity to reduce persistent firing. Chronic stress exposures can further exacerbate these signaling events leading to loss of spines and resulting in marked cognitive impairment. In this review, we discuss how stress signaling mechanisms can lead to spine loss, including changes to BDNF-mTORC1 signaling, calcium homeostasis, actin dynamics, and mitochondrial actions that engage glial removal of spines through inflammatory signaling. Stress signaling events may be amplified in PFC spines due to cAMP magnification of internal calcium release. As PFC dendritic spine loss is a feature of many cognitive disorders, understanding how stress affects the structure and function of the PFC will help to inform strategies for treatment and prevention. 

Although mouse models of Alzheimer’s disease (AD) have provided tremendous breakthroughs, the etiology of later onset AD remains unknown. In particular, tau pathology in the association cortex is poorly replicated in mouse models. Aging rhesus monkeys naturally develop cognitive deficits, amyloid plaques, and the same qualitative pattern and sequence of tau pathology as humans, with tangles in the oldest animals. Thus, aging rhesus monkeys can play a key role in AD research. For example, aging monkeys can help reveal how synapses in the prefrontal association cortex are uniquely regulated compared to the primary sensory cortex in ways that render them vulnerable to calcium dysregulation and tau phosphorylation, resulting in the selective localization of tau pathology observed in AD. The ability to assay early tau phosphorylation states and perform high-quality immunoelectron microscopy in monkeys is a great advantage, as one can capture early-stage degeneration as it naturally occurs in situ. Our immunoelectron microscopy studies show that phosphorylated tau can induce an “endosomal traffic jam” that drives amyloid precursor protein cleavage to amyloid-β in endosomes. As amyloid-β increases tau phosphorylation, this creates a vicious cycle where varied precipitating factors all lead to a similar phenotype. These data may help explain why circuits with aggressive tau pathology (e.g., entorhinal cortex) may degenerate prior to producing significant amyloid pathology. Aging monkeys therefore can play an important role in identifying and testing potential therapeutics to protect the association cortex, including preventive therapies that are challenging to test in humans.