NAP (davunetide) rescues neuronal dysfunction in a Drosophila model of tauopathy

Alzheimer’s disease (AD) is a devastating neurodegenerative disease causing irreversible cognitive decline in the elderly. There is no disease-modifying therapy for this condition and the mechanisms underpinning neuronal dysfunction and neurodegeneration are unclear. Compromised cytoskeletal integrity within neurons is reported in AD. This is believed to result from loss-of-function of the microtubule-associated protein tau, which becomes hyper-phosphorylated and deposits into neurofibrillary tangles in AD. We have developed a Drosophila model of tauopathy in which abnormal human tau mediates neuronal dysfunction characterised by microtubule destabilisation, axonal transport disruption, synaptic defects and behavioural impairments. Here we show that a microtubule-stabilising drug, NAPVSIPQ (NAP), prevents as well as reverses these phenotypes even after they have become established. Moreover, it does not alter abnormal tau levels indicating that it by-passes toxic tau altogether. Thus, microtubule stabilisation is a disease-modifying therapeutic strategy protecting against tau-mediated neuronal dysfunction, which holds great promise for tauopathies like AD

Therapeutic applications of computer models of brain activity for Alzheimer disease.

THERAPEUTIC IMPLICATIONS OF COMPUTER MODELS OF BRAIN ACTIVITY FOR ALZHEIMER DISEASE

Monoaminergic Neuropathology in Alzheimer's disease

Acknowledgments This work was supported by The Croatian Science Foundation grant. no. IP-2014-09-9730 (“Tau protein hyperphosphorylation, aggregation, and trans-synaptic transfer in Alzheimer’s disease: cerebrospinal fluid analysis and assessment of potential neuroprotective compounds”) and European Cooperation in Science and Technology (COST) Action CM1103 (“Stucture-based drug design for diagnosis and treatment of neurological diseases: dissecting and modulating complex function in the monoaminergic systems of the brain”). PRH is supported in part by NIH grant P50 AG005138.Peer reviewedPostprin

Advancements in understanding and addressing Alzheimer's disease: a comprehensive review

Alzheimer's disease (AD) presents a multifaceted challenge in the realm of neurodegenerative disorders, affecting millions globally and posing significant burdens on patients, caregivers, and healthcare systems alike. Over a century of research has illuminated various facets of AD pathophysiology, highlighting the intricate interplay between genetic, molecular, and environmental factors in disease progression. This comprehensive review synthesized key findings from recent literature, encompassing diverse topics ranging from diagnostic challenges and emerging therapeutic approaches to caregiver support and evolving research strategies. Furthermore, it explored the complexities of AD pathogenesis, elucidating the role of amyloid-beta (Aβ) plaques, tau protein pathology, neuroinflammation, and mitochondrial dysfunction in neuronal degeneration. Therapeutic interventions for AD, both current and emerging, are critically evaluated, with a focus on pharmacological agents targeting Aβ aggregation, tau pathology, and synaptic dysfunction. Non-pharmacological strategies, including lifestyle modifications and cognitive interventions, are also explored for their potential in disease management. Finally, the review examined the landscape of AD research, highlighting ongoing efforts to elucidate disease mechanisms, identify novel therapeutic targets, and address existing gaps in prevention and treatment strategies. It emphasizes the need for collaborative endeavours among stakeholders to accelerate progress towards effective AD management and ultimately, improve outcomes for affected individuals and their families. Through its comprehensive synthesis of current knowledge and future directions, this review aims to inform clinicians, researchers, policymakers, and advocates involved in the fight against Alzheimer's disease, offering insights that may catalyse advancements in diagnosis, treatment, and care

A BIOLOGICAL-PSYCHOLOGICAL VIEW ON AGEING

In this paper two major views on ageing: the ‘genetic’ (‘programmed’) types of theories and the ‘wear-and-tear’ (‘damage’ or ‘error’) theories are presented. The genetic theories, saying that specific genes regulate ageing, explain the species differences better, while the wear-and-tear theories, implying that damages in the genome lead to ageing, explain the male-female differences better. The ‘survival curve’ (human’s survival as a function of time), shows that the maximum age is fixed, but that the average age still increases. Good food, a safe hygienic environment and adequate medical care play a positive role in human longevity. Notwithstanding that it can be stated that ageing is associated with somatic and, in particular, with cognitive decline. Brain degeneration as expressed in the diseases of Alzheimer and Parkinson are rather typical ageing disorders. However, natural ageing is also accompanied by mental and physical decline, presumably due to brain cell loss and loss of contacts between nerve cells. Presently, it becomes more and more clear that the decline due to ageing can be delayed or slowed down to a certain degree. Keeping the body and the brain active might be associated by a reduction in the loss of synapses, or even in the formation of extra synapses. This forms a compensation buffer for the decrease of general bodily processes, including cognitive functions. Especially, elderly people complain about memory problems. The memory decline is particularly in episodic memory. However, the procedural memory (for the performance of complex activities and skills) does not decline and the semantic memory (the memory concerned with meanings and concepts) even sometimes profits of the rise in age. Though old people have episodic memory problems, they have compensating types of memory, which delivers them to have an adequate response to life situations. This can be regarded as an increase in wisdo

A BIOLOGICAL-PSYCHOLOGICAL VIEW ON AGEING

In this paper two major views on ageing: the ‘genetic’ (‘programmed’) types of theories and the ‘wear-and-tear’ (‘damage’ or ‘error’) theories are presented. The genetic theories, saying that specific genes regulate ageing, explain the species differences better, while the wear-and-tear theories, implying that damages in the genome lead to ageing, explain the male-female differences better. The ‘survival curve’ (human’s survival as a function of time), shows that the maximum age is fixed, but that the average age still increases. Good food, a safe hygienic environment and adequate medical care play a positive role in human longevity. Notwithstanding that it can be stated that ageing is associated with somatic and, in particular, with cognitive decline. Brain degeneration as expressed in the diseases of Alzheimer and Parkinson are rather typical ageing disorders. However, natural ageing is also accompanied by mental and physical decline, presumably due to brain cell loss and loss of contacts between nerve cells. Presently, it becomes more and more clear that the decline due to ageing can be delayed or slowed down to a certain degree. Keeping the body and the brain active might be associated by a reduction in the loss of synapses, or even in the formation of extra synapses. This forms a compensation buffer for the decrease of general bodily processes, including cognitive functions. Especially, elderly people complain about memory problems. The memory decline is particularly in episodic memory. However, the procedural memory (for the performance of complex activities and skills) does not decline and the semantic memory (the memory concerned with meanings and concepts) even sometimes profits of the rise in age. Though old people have episodic memory problems, they have compensating types of memory, which delivers them to have an adequate response to life situations. This can be regarded as an increase in wisdo

Ontogenetic and Phylogenetic Approaches for Studying the Mechanisms of Cognitive Dysfunctions

This chapter summarizes the phylogenetic and ontogenetic approaches for studying cognitive disorders such as Alzheimer’s disease. It gives an extended example of evaluation of animal behavior and brain properties using an original model of prenatal hypoxia in rats by various physiological, behavioral, immunohistochemical, molecular biological, and biochemical techniques at different stages of postnatal development, which provide a better understanding of the pathological processes in the human brain during the development of neurodegeneration

Painless Nerve Growth Factor: A TrkA biased agonist mediating a broad neuroprotection via its actions on microglia cells

Abstract Nerve Growth Factor (NGF) is a therapeutic candidate for Alzheimer's disease, based on its well known actions on basal forebrain cholinergic neurons. However, because of its pro-nociceptive activity, in current clinical trials NGF has to be administered intraparenchymally into the brain by neurosurgery via cell or gene therapy approaches. To prevent the NGF pain-inducing collateral effects, thus avoiding the necessity for local brain injection, we developed painless NGF (hNGFp), based on the human genetic disease Hereditary Sensory and Autonomic Neuropathy type V (HSAN V). hNGFp has similar neurotrophic activity as wild type human NGF, but its pain sensitizing activity is tenfold lower. Pharmacologically, hNGFp is a biased receptor agonist of NGF TrkA receptor. The results of recent studies shed new light on the neuroprotective mechanism by hNGFp and are highly relevant for the planning of NGF-based clinical trials. The intraparenchymal delivery of hNGFp, as used in clinical trials, was simulated in the 5xFAD mouse model and found to be inefficacious in reducing Aβ plaque load. On the contrary, the same dose of hNGFp administered intranasally, which was rather widely biodistributed in the brain and did not induce pain sensitization, blocked APP processing into amyloid and restored synaptic plasticity and memory in this aggressive neurodegeneration model. This potent and broad neuroprotection by hNGFp was found to be mediated by hNGFp actions on glial cells. hNGFp increases inflammatory proteins such as the soluble TNFα receptor II and the chemokine CXCL12. Independent work has shown that NGF has a potent anti-inflammatory action on microglia and steers them towards a neuroprotective phenotype. These studies demonstrate that microglia cells are a new target cell of NGF in the brain and have therapeutic significance: i) they establish that the neuroprotective actions of hNGFp relies on a widespread exposure of the brain, ii) they identify a new anti-neurodegenerative pathway, linking hNGFp to inflammatory chemokines and cytokines via microglia, a common target for new therapeutic opportunities for neurodegenerative diseases, iii) they extend the neuroprotective potential of hNGFp beyond its classical cholinergic target, thereby widening the range of neurological diseases for which this neurotrophic factor might be used therapeutically, iv) they help interpreting the results of current NGF clinical trials in AD and the design of future trials with this new potent therapeutic candidate