The Cause of Alzheimer's Disease: The Theory of Multipathology Convergence to Chronic Neuronal Stress.

The field of Alzheimer's disease (AD) research critically lacks an all-inclusive etiology theory that would integrate existing hypotheses and explain the heterogeneity of disease trajectory and pathologies observed in each individual patient. Here, we propose a novel comprehensive theory that we named: the multipathology convergence to chronic neuronal stress. Our new theory reconsiders long-standing dogmas advanced by previous incomplete theories. Firstly, while it is undeniable that amyloid beta (Aß) is involved in AD, in the seminal stage of the disease Aß is unlikely pathogenic. Instead, we hypothesize that the root cause of AD is neuronal stress in the central nervous system (CNS), and Aß is expressed as part of the physiological response to protect CNS neurons from stress. If there is no return to homeostasis, then Aß becomes overexpressed, and this includes the generation of longer forms that are more toxic and prone to oligomerization. Secondly, AD etiology is plausibly not strictly compartmentalized within the CNS but may also result from the dysfunction of other physiological systems in the entire body. This view implies that AD may not have a single cause, but rather needs to be considered as a spectrum of multiple chronic pathological modalities converging to the persistent stressing of CNS neurons. These chronic pathological modalities, which include cardiovascular disease, metabolic disorders, and CNS structural changes, often start individually, and over time combine with other chronic modalities to incrementally escalate the amount of stress applied to CNS neurons. We present the case for considering Aß as a marker of neuronal stress in response to hypoxic, toxic, and starvation events, rather than solely a marker of AD. We also detail numerous human chronic conditions that can lead to neuronal stress in the CNS, making the link with co-morbidities encountered in daily clinical AD practice. Finally, we explain how our theory could be leveraged to improve clinical care for AD and related dementia in personalized medicine paradigms in the near future.

GluN3-Containing NMDA Receptors in the Rat Nucleus Accumbens Core Contribute to Incubation of Cocaine Craving.

Cue-induced cocaine craving progressively intensifies (incubates) after withdrawal from cocaine self-administration in rats and humans. In rats, the expression of incubation ultimately depends on Ca2+-permeable AMPARs that accumulate in synapses onto medium spiny neurons (MSNs) in the NAc core. However, the delay in their accumulation (∼1 month after drug self-administration ceases) suggests earlier waves of plasticity. This prompted us to conduct the first study of NMDAR transmission in NAc core during incubation, focusing on the GluN3 subunit, which confers atypical properties when incorporated into NMDARs, including insensitivity to Mg2+ block and Ca2+ impermeability. Whole-cell patch-clamp recordings were conducted in MSNs of adult male rats 1-68 d after discontinuing extended-access saline or cocaine self-administration. NMDAR transmission was enhanced after 5 d of cocaine withdrawal, and this persisted for at least 68 d of withdrawal. The earliest functional alterations were mediated through increased contributions of GluN2B-containing NMDARs, followed by increased contributions of GluN3-containing NMDARs. As predicted by GluN3-NMDAR incorporation, fewer MSN spines exhibited NMDAR-mediated Ca2+ entry. GluN3A knockdown in NAc core was sufficient to prevent incubation of craving, consistent with biotinylation studies showing increased GluN3A surface expression, although array tomography studies suggested that adaptations involving GluN3B also occur. Collectively, our data show that a complex cascade of NMDAR and AMPAR plasticity occurs in NAc core, potentially through a homeostatic mechanism, leading to persistent increases in cocaine cue reactivity and relapse vulnerability. This is a remarkable example of experience-dependent glutamatergic plasticity evolving over a protracted window in the adult brain.SIGNIFICANCE STATEMENT "Incubation of craving" is an animal model for the persistence of vulnerability to cue-induced relapse after prolonged drug abstinence. Incubation also occurs in human drug users. AMPAR plasticity in medium spiny neurons (MSNs) of the NAc core is critical for incubation of cocaine craving but occurs only after a delay. Here we found that AMPAR plasticity is preceded by NMDAR plasticity that is essential for incubation and involves GluN3, an atypical NMDAR subunit that markedly alters NMDAR transmission. Together with AMPAR plasticity, this represents profound remodeling of excitatory synaptic transmission onto MSNs. Given the importance of MSNs for translating motivation into action, this plasticity may explain, at least in part, the profound shifts in motivated behavior that characterize addiction.

Variability in sub-threshold signaling linked to Alzheimer's disease emerges with age and amyloid plaque deposition in mouse ventral CA1 pyramidal neurons.

The hippocampus is vulnerable to deterioration in Alzheimer's disease (AD). It is, however, a heterogeneous structure, which may contribute to the differential volumetric changes along its septotemporal axis during AD progression. Here, we investigated amyloid plaque deposition along the dorsoventral axis in two strains of transgenic AD (ADTg) mouse models. We also used patch-clamp physiology in these mice to probe for functional consequences of AD pathogenesis in ventral hippocampus, which we found bears significantly higher plaque burden in the aged ADTg group compared to corresponding dorsal regions. Despite dorsoventral differences in amyloid load, ventral CA1 pyramidal neurons of aged ADTg mice exhibited subthreshold physiological changes similar to those previously reported in dorsal neurons, indicative of an HCN channelopathy, but lacked exacerbated suprathreshold accommodation. Additionally, HCN channel function could be rescued by pharmacological manipulation of the endoplasmic reticulum. These observations suggest that an AD-linked HCN channelopathy emerges in both dorsal and ventral CA1 pyramidal neurons, but that the former encounter an additional integrative obstacle in the form of reduced intrinsic excitability.

Cognitive aging is associated with redistribution of synaptic weights in the hippocampus.

Behaviors that rely on the hippocampus are particularly susceptible to chronological aging, with many aged animals (including humans) maintaining cognition at a young adult-like level, but many others the same age showing marked impairments. It is unclear whether the ability to maintain cognition over time is attributable to brain maintenance, sufficient cognitive reserve, compensatory changes in network function, or some combination thereof. While network dysfunction within the hippocampal circuit of aged, learning-impaired animals is well-documented, its neurobiological substrates remain elusive. Here we show that the synaptic architecture of hippocampal regions CA1 and CA3 is maintained in a young adult-like state in aged rats that performed comparably to their young adult counterparts in both trace eyeblink conditioning and Morris water maze learning. In contrast, among learning-impaired, but equally aged rats, we found that a redistribution of synaptic weights amplifies the influence of autoassociational connections among CA3 pyramidal neurons, yet reduces the synaptic input onto these same neurons from the dentate gyrus. Notably, synapses within hippocampal region CA1 showed no group differences regardless of cognitive ability. Taking the data together, we find the imbalanced synaptic weights within hippocampal CA3 provide a substrate that can explain the abnormal firing characteristics of both CA3 and CA1 pyramidal neurons in aged, learning-impaired rats. Furthermore, our work provides some clarity with regard to how some animals cognitively age successfully, while others' lifespans outlast their "mindspans."

The application of in vitro-derived human neurons in neurodegenerative disease modeling.

The development of safe and effective treatments for age-associated neurodegenerative disorders is an on-going challenge faced by the scientific field. Key to the development of such therapies is the appropriate selection of modeling systems in which to investigate disease mechanisms and to test candidate interventions. There are unique challenges in the development of representative laboratory models of neurodegenerative diseases, including the complexity of the human brain, the cumulative and variable contributions of genetic and environmental factors over the course of a lifetime, inability to culture human primary neurons, and critical central nervous system differences between small animal models and humans. While traditional rodent models have advanced our understanding of neurodegenerative disease mechanisms, key divergences such as the species-specific genetic background can limit the application of animal models in many cases. Here we review in vitro human neuronal systems that employ stem cell and reprogramming technology and their application to a range of neurodegenerative diseases. Specifically, we compare human-induced pluripotent stem cell-derived neurons to directly converted, or transdifferentiated, induced neurons, as both model systems can take advantage of patient-derived human tissue to produce neurons in culture. We present recent technical developments using these two modeling systems, as well as current limitations to these systems, with the aim of advancing investigation of neuropathogenic mechanisms using these models.

Targeting the Cholinergic System to Develop a Novel Therapy for Huntington's Disease.

In this review, we outline the role of the cholinergic system in Huntington's disease, and briefly describe the dysfunction of cholinergic transmission, cholinergic neurons, cholinergic receptors and cholinergic survival factors observed in post-mortem human brains and animal models of Huntington's disease. We postulate how the dysfunctional cholinergic system can be targeted to develop novel therapies for Huntington's disease, and discuss the beneficial effects of cholinergic therapies in pre-clinical and clinical studies.