623 Apolipoprotein E-Derived 22 kDa fragment neurotoxicity: A new pathophysiological mechanism in Alzheimer's disease

The three common apolipoprotein E (ApoE) alleles differentially contribute to the risk of Alzheimer's disease (AD). While the APOE genotype alters susceptibility to disease expression, individuals with APOE ϵ4 alleles have the highest risk of developing AD; the APOE ϵ4 allele is neither essential nor sufficient on its own to cause AD. Since the discovery, in 1992, of the involvement of APOE in AD, many scientists have explored the role of the ApoE isoforms in the central nervous system in an effort to elucidate their roles in the pathophysiological mechanism of this disease. While many hypotheses have been proposed, none has been proven. ApoE was discovered through investigations into cholesterol metabolism. In serum and in cerebrospinal fluid ApoE binds lipoprotein particles, which contain cholesterol esters, and is critical in the shuttling of cholesterol from cell to cell. Trafficking of ApoE is mediated by specific interactions with cell-surface receptors. As described later, several families of ApoE receptors with diverse functions have been discovered. The roles of these receptors are proving increasingly complex since additional interactions with other ligands and with other intracellular proteins are rapidly being identified. It was once thought that these receptors only shuttle ApoE-containing phospholipid particles from the extracellular environment into the cell, but they also transduce a number of additional intracellular signals and interactions. Molecular signalling cascades initiated by the various ApoE receptors modulate a number of critical cellular processes. To date, two functional classes of ApoE receptors have been identified. The first is the low-density lipoprotein receptor family and the second the scavenger receptor families.

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Relationship between apolipoprotein E and the amyloid deposits and dystrophic neurites of Alzheimer's disease

Neuropathology and Applied Neurobiology ◽

10.1046/j.1365-2990.1997.00072.x ◽

1997 ◽

Vol 23 (6) ◽

pp. 483-491 ◽

Cited By ~ 1

Author(s):

T. C. Dickson ◽

H. L. Saunders ◽

J. C. Vickers

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Apolipoprotein E ◽

Dystrophic Neurites ◽

Amyloid Deposits

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Age Modifies the Association Between Apolipoprotein E Genotype and Alzheimer's Disease: A CSF Biomarker-Based Multicentric Case-Control Study

SSRN Electronic Journal ◽

10.2139/ssrn.3417885 ◽

2019 ◽

Author(s):

Hana Sadikki ◽

Aurore Fayosse ◽

Emmanuel Cognat ◽

Séverine Sabia ◽

Sebastiaan Engelborghs ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Apolipoprotein E ◽

Case Control Study ◽

Case Control ◽

Csf Biomarker ◽

Control Study ◽

Apolipoprotein E Genotype

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An Insight in Pathophysiological Mechanism of Alzheimer’s Disease and its Management using Plant Natural Products

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666200730155928 ◽

2020 ◽

Vol 20 ◽

Author(s):

Zeba Firdaus ◽

Tryambak Deo Singh

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Natural Products ◽

Side Effects ◽

Neuronal Degeneration ◽

Acetylcholinesterase Inhibitor ◽

Pathophysiological Mechanism ◽

Limited Effectiveness ◽

Drug Development Research ◽

Sites Of Action

: Alzheimer’s disease (AD) is an age-associated nervous system disorder and a leading cause of dementia worldwide. Clinically it is described by cognitive impairment, and pathophysiologically by deposition of amyloid plaques and neurofibrillary tangles in the brain and neurodegeneration. This article reviews the pathophysiology, course of neuronal degeneration, and the various possible hypothesis of AD progression. These hypotheses include amyloid cascade, tau hyperphosphorylation, cholinergic disruption, metal dysregulation, vascular dysfunction, oxidative stress, and neuroinflammation. There is an exponential increase in the occurrence of the AD in recent few years that indicate an urgent need to develop some effective treatment. Currently, only 2 classes of drugs are available for AD treatment namely acetylcholinesterase inhibitor and NMDA receptor antagonist. Since AD is a complex neurological disorder and these drugs use a single target approach, alternatives are needed due to limited effectiveness and unpleasant side-effects of these drugs. Currently, plants have been used for drug development research especially because of their multiple sites of action and fewer side effects. Uses of some herbs and phytoconstituents for the management of neuronal disorders like AD have been documented in this article. Phytochemical screening of these plants shows the presence of many beneficial constituents like flavonoids, triterpenes, alkaloids, sterols, polyphenols, and tannins. These compounds show a wide array of pharmacological activities such as anti-amyloidogenic, anticholinesterase, and antioxidant. This article summarizes the present understanding of AD progression and gathers biochemical evidence from various works on natural products that can be useful in the management of this disease.

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Crossed Cerebellar Diaschisis in Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205015666180913102615 ◽

2018 ◽

Vol 15 (13) ◽

pp. 1267-1275 ◽

Cited By ~ 1

Author(s):

F.E. Reesink ◽

D. Vállez García ◽

C.A. Sánchez-Catasús ◽

D.E. Peretti ◽

A.T. Willemsen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Left Hemisphere ◽

Pet Imaging ◽

Fdg Pet ◽

Pathophysiological Mechanism ◽

Crossed Cerebellar Diaschisis ◽

Amyloid Accumulation ◽

Cerebellar Diaschisis ◽

18F Fdg

Background: We describe the phenomenon of crossed cerebellar diaschisis (CCD) in four subjects diagnosed with Alzheimer’s disease (AD) according to the National Institute on Aging - Alzheimer Association (NIA-AA) criteria, in combination with 18F-FDG PET and 11C-PiB PET imaging. Methods: 18F-FDG PET showed a pattern of cerebral metabolism with relative decrease most prominent in the frontal-parietal cortex of the left hemisphere and crossed hypometabolism of the right cerebellum. 11C-PiB PET showed symmetrical amyloid accumulation, but a lower relative tracer delivery (a surrogate of relative cerebral blood flow) in the left hemisphere. CCD is the phenomenon of unilateral cerebellar hypometabolism as a remote effect of supratentorial dysfunction of the brain in the contralateral hemisphere. The mechanism implies the involvement of the cortico-ponto-cerebellar fibers. The pathophysiology is thought to have a functional or reversible basis but can also reflect in secondary morphologic change. CCD is a well-recognized phenomenon, since the development of new imaging techniques, although scarcely described in neurodegenerative dementias. Results: To our knowledge this is the first report describing CCD in AD subjects with documentation of both 18F-FDG PET and 11C-PiB PET imaging. CCD in our subjects was explained on a functional basis due to neurodegenerative pathology in the left hemisphere. There was no structural lesion and the symmetric amyloid accumulation did not correspond with the unilateral metabolic impairment. Conclusion: This suggests that CCD might be caused by non-amyloid neurodegeneration. The pathophysiological mechanism, clinical relevance and therapeutic implications of CCD and the role of the cerebellum in AD need further investigation.

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