Current Experimental Therapy for Alzheimers Disease

Alzheimer’s disease (AD) is the most common neurodegenerative disorder. Worldwide prevalence of the disease is estimated at more than 24 million cases. With aging of populations, this number will likely increase to more than 80 million cases by the year 2040. The annual incidence worldwide is estimated at 4.6 million cases which is the equivalent of one new case every seven seconds! The pathophysiology of AD is complex and largely misunderstood. It is thought to start with the accumulation of beta-amyloid (Aβ) that leads to deposition of insoluble neuritic or senile plaques. Secondary events in this “amyloid cascade” include hyperphosphorylation of the protein tau into neurofibrillary tangles, inflammation, oxidation, and excitotoxicity that eventually cause activation of apoptotis, cell death and neurotransmitter deficits. This review will briefly summarize recent advances in the pathophysiology of AD and focus on the pharmacological treatment of the cognitive and functional symptoms of AD. It will discuss the roles of vascular prevention, cholinesterase inhibitors and an NMDA-antagonist in the management of AD. It will address the issues thought to be related to the lack of persistence or discontinuation of therapy with cholinesterase inhibitors shown in recent studies and some of the solutions proposed. These include setting realistic expectations in light of a neurodegenerative condition and available symptomatic treatments, slowly titrating medications, and using alternate routes of administration. Finally, it will introduce future therapeutic options currently under study.

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“…Other agents being tested target oxidative stress in AD, neuroinflammation, cholesterol metabolism and the neuroendocrine pathways [ 22 , 71 ].…”

Section: Future Treatmentsmentioning

confidence: 99%

Update on the Pharmacological Treatment of Alzheimers Disease

Massoud¹,

Gauthier²

2010

138

101

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“…To combat AD, considerable effort has been directed towards developing a variety of therapeutic strategies (Jakob-Roetne and Jacobsen, 2009;Rafii and Aisen, 2009;Vardy et al, 2005). One branch of this research is focused on preventing the formation of A␤ by the development of ␤-and ␥-secretase inhibitors or on strategies for directly antagonizing A␤ accumulation, using either "plaque-buster" drugs or immunotherapy to aid in clearing the brain of plaques (Chen et al, 2007;Gandy, 2005). Given that the abnormal accumulation of A␤ in the brain can be attributed to increased production or decreased degradation of A␤, the activation of specific proteases that metabolize A␤, thereby clearing it from the brain, may be a potential treatment for AD (Eckman and Eckman, 2005;El-Amouri et al, 2008;Nalivaeva et al, 2008;Turner and Nalivaeva, 2007;Wang et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

A highly sensitive peptide substrate for detecting two Aβ-degrading enzymes: Neprilysin and insulin-degrading enzyme

Chen

Liao

et al. 2010

Journal of Neuroscience Methods

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“…However, many of these approaches are fraught with toxic side effects when tested in vivo. Beyond the limited FDA-approved drugs, other methods, such as β-sheet blockers, as anti-amyloid compounds, and immunotherapies have been developed to counter AD-induced pathology [14,15].…”

Section: Introductionmentioning

confidence: 99%

Preservation of dendritic spine morphology and postsynaptic signaling markers after treatment with solid lipid curcumin particles in the 5xFAD mouse model of Alzheimer’s disease

Maiti¹,

Dunbar²

2020

Preprint

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Background Synaptic failure is one of the principal events associated with cognitive dysfunction in Alzheimer’s disease (AD). Preservation of existing synapses and prevention of synaptic loss are promising strategies to preserve cognitive function in AD patients. As a potent natural anti-oxidant, anti-amyloid, anti-inflammatory polyphenol, curcumin (Cur) shows great promise as a therapy for AD. However, hydrophobicity of natural Cur limits its solubility, stability, bioavailability and clinical utility for AD therapy. We have demonstrated that solid lipid curcumin particles (SLCP) have greater therapeutic potential than natural Cur in vitro and in vivo models of AD. In the present study, we have investigated whether SLCP has any preservative role on affected dendritic spines and synaptic markers in 5xFAD mice.Methods Six- and 12-month-old 5xFAD and age-matched wild-type mice received oral administration of SLCP (100 mg/kg body weight) or equivalent amounts of vehicle for 2 months. Neuronal morphology, neurodegeneration and amyloid plaque load were investigated from prefrontal cortex (PFC), entorhinal cortex (EC), CA1, CA3 and the subicular complex (SC). Further, dendritic spine density of apical and basal branches were studied by Golgi-Cox stain. Further, synaptic markers, such as synaptophysin, PSD95, Shank, Homer, Drebrin, kalirin-7, CREB and phosphorylated CREB (pCREB) were studied using Western blots. Finally, cognitive and motor functions were assessed using open field, novel object recognition (NOR) and Morris water maze (MWM) tasks after treatment with SLCP.Results We observed an increase number of pyknotic and degenerated cells in all these brain areas in 5xFAD mice and SLCP treatment partially protected against those losses. Decrease in dendritic arborization and dendritic spine density from primary and secondary apical and basal branches were observed in PFC, EC, CA1, CA3 in both 6- and 12-month-old 5xFAD mice and SLCP treatments partially preserved the normal morphology of these dendritic spines. In addition, pre- and post-synaptic protein markers were also restored by SLCP treatment. Furthermore, SLCP treatment improved NOR and cognitive function in 5xFAD mice.Conclusions Overall, these findings indicate that use of SLCP exerts neuroprotective properties by decreasing amyloid plaque burden, preventing neuronal death, as well as preservation of dendritic spine density and synaptic markers in the 5xFAD mice.

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Current Experimental Therapy for Alzheimers Disease

Cited by 13 publications

References 95 publications

Update on the Pharmacological Treatment of Alzheimers Disease

Update on the Pharmacological Treatment of Alzheimers Disease

A highly sensitive peptide substrate for detecting two Aβ-degrading enzymes: Neprilysin and insulin-degrading enzyme

Preservation of dendritic spine morphology and postsynaptic signaling markers after treatment with solid lipid curcumin particles in the 5xFAD mouse model of Alzheimer’s disease

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