The nervous system
Laurie K. McCorry, Martin M. Zdanowicz, Cynthia Y. Gonnella in Essentials of Human Physiology and Pathophysiology for Pharmacy and Allied Health, 2019
Although the exact cause of Alzheimer’s disease is still uncertain, great strides have been made in recent years to enhance our understanding of the disease process. Two pathologic “hallmarks” found in the brains of patients with Alzheimer’s disease are the presence of beta amyloid plaques, and neurofibrillary tangles. Beta amyloid plaques form from accumulations of a brain protein called amyloid beta. This protein is derived from a larger protein called amyloid precursor protein (APP). There is evidence that improper cleavage or “proteolysis” of the APP leads to the formation of amyloid beta proteins that subsequently accumulate in CNS neurons and alters their function. Neurofibrillary tangles are twisted accumulations of a protein called tau that form in the cytoplasm of affected neurons. Because the cytoplasm is essential for the transport of nutrients and other essential substances in the neuron, the presence of neurofibrillary tangles may interfere with this and damage the neuron.
Many Applications of Hemp in Neurological & Gut-Brain Axis *
Betty Wedman-St Louis in Cannabis as Medicine, 2019
The involvement of CB2 receptors in Alzheimer’s disease was demonstrated in a number of human studies. Inspections of post-mortem brains from individuals with Alzheimer’s disease showed that CB2 receptors are upregulated in cells that are linked to amyloid beta (Aβ)-enriched neuritic plaques.7–10 The deposition of amyloid beta plaques in the brain is involved in Alzheimer’s disease pathology. Other researchers found markedly higher CB2 receptor levels in individuals with severe Alzheimer’s disease compared with age-matched controls or people with moderate Alzheimer’s.11 Activation of the CB2 receptor has resulted in beneficial effects in Alzheimer’s disease, including the inhibition of microglial activation in mice.12
Introduction
Lars-Göran Nilsson, Nobuo Ohta in Dementia and Memory, 2013
It has often been claimed that cognitive performance alone might serve as a satisfactory mean for identifying individuals early who will later develop dementia. In line with Rabbitt (this volume), it is argued in the present chapter that this is hardly not so. In an ongoing study in the Betula project, we identified 10 participants who maintained their performance at a stable level across a 10-year period including three test occasions and 10 participants who had declined in performance across the same period of time. All participants were between 50 and 65 years of age, and they were all non-demented. The prediction was that those who had declined in performance would have more beta-amyloid in their brains when we had them undergo a positron emission tomography (PET) examination. In previous research, it has been claimed that beta-amyloid is a significant feature of those who has been diagnosed as having Alzheimer’s disease (AD). Our results showed that there was no difference between the two groups with respect to levels of beta-amyloid. This might mean that cognitive performance is a poor predictor of Alzheimer’s disease, or it might mean that beta-amyloid is not an early marker for AD. It might mean that the amyloid cascade occurs much later, perhaps quite close in time to the diagnosis. We will therefore follow up these participants in a new PET examination five years after the previous PET occasion.
Amyloid beta (1–42) downregulates adenosine-2b receptors in addition to mitochondrial impairment and cholinergic dysfunction in memory-sensitive mouse brain regions
Published in Journal of Receptors and Signal Transduction, 2020
Bhupesh Chandra Semwal, Debapriya Garabadu
It has been well documented that the aggregation of amyloid beta (Aβ) in the brain is one of the hallmarks of the pathophysiology of AD [5]. It is also suggested that the aggregation of Aβ can cause degeneration of cholinergic neurons in several areas, including forebrain and hippocampus of the AD brain [6]. The mitochondrial abnormalities include mitochondrial deoxyribonucleic acid (mtDNA) damage, dysfunctional mtDNA expression, increased mtDNA mutations, reduced mtDNA copies, increased oxidative damage [7], reduced mitochondrial axonal transport, and overall impaired mitochondrial dynamics in memory-sensitive brain regions during AD [8–10]. It is also suggested that Aβ aggregation induces mitochondrial dysfunction which can ultimately lead to synaptic dysregulation including cholinergic synapses in the memory-sensitive brain areas in the pathophysiology of AD [11,12]. It has been documented that drugs that treat the cholinergic dysfunction can also reduce mitochondrial toxicity in the experimental animals. Therefore, it can be assumed that cholinergic dysfunction, mitochondrial impairment and Aβ aggregation may form a vicious cycle in the pathogenesis of AD.
The aquaporin-4 water channel and updates on its potential as a drug target for Alzheimer’s disease
Published in Expert Opinion on Therapeutic Targets, 2023
Bret Silverglate, Xiaoyi Gao, Hannah P. Lee, Peter Maliha, George T. Grossberg
Alzheimer’s disease (AD) is the most common cognitive disorder in older adults. AD pathogenesis has long been associated with the formation of amyloid plaques and neurofibrillary tangles (NFTs). Amyloid plaques have detrimental effects on synaptic function and are composed of beta-amyloid proteins, which originate from amyloid precursor protein (APP). The insoluble NFTs consist of hyperphosphorylated tau and are also neurotoxic. Aquaporin channels (AQPs) are transmembrane proteins that function as bidirectional water and small solute channels. There are 13 classes of AQPs expressed in humans (AQPs 0–12). AQP4 channels expressed in human brain tissue are vital in clearing interstitial solutes, metabolic products, and protein aggregates (including the Aβ and hyperphosphorylated tau proteins mentioned above) from the brain via the glymphatic system, thus raising interest in its possible contribution to AD pathogenesis, and, importantly, in its potential pharmacologic targeting as treatment of AD [1,2].
Delivery of neurotrophic factors in the treatment of age-related chronic neurodegenerative diseases
Published in Expert Opinion on Drug Delivery, 2020
Smrithi Padmakumar, Maie S. Taha, Ekta Kadakia, Benjamin S. Bleier, Mansoor M. Amiji
However, the failure of major clinical trials considering the brain amyloid protein for AD therapy with secretase inhibitors and Aβ monomer/fibril directed immunotherapy strategies deserves attention in the current scenario, which also emphasizes the need for more research into other potential targets [8]. On the contrary, there have been recent reports suggesting the relation of AD pathogenesis to toxic and soluble amyloid-beta oligomers (AßO), rather than its insoluble forms such as plaques and fibrils. These have been pointed out as major triggering factors for the loss of neurons and synaptic dysfunction observed particularly in patients with AD [9]. Therefore, those studies investigating more of Aβ oligomer selective antibodies capable of neutralizing the residual toxic traces in brain should be given more attention.
Related Knowledge Centers
- Peptide
- Amino Acid
- Amyloid Plaques
- Alzheimer's Disease
- Amyloid-Beta Precursor Protein
- Beta-Secretase 1
- Gamma Secretase
- Substrate Presentation
- Oligomer
- Prion