Date of Presentation

5-5-2022 12:00 AM

College

School of Osteopathic Medicine

Poster Abstract

Altered lipid metabolism is implicated in the risk of sporadic Alzheimer’s disease (AD) and related dementias (ADRD); however, the precise mechanisms accounting for findings from observational studies remains to be fully elucidated.

Plasmalogens are a subclass of integral membrane phospholipids with unique properties that appear to play important roles relevant to the pathophysiology of AD and ADRD, including vesicle fusion necessary for synaptic neurotransmitter release, modulation of membrane fluidity and microdomain dynamics, membrane antioxidant functions, and neuroprotection. Like the more familiar phosphatides, plasmalogens are synthesized on a 3-carbon glycerol backbone; however, they differ from phosphatides by the presence of a vinyl ether linkage at the 1st (sn1) glycerol carbon atom in place of the acyl ester linkage present at sn1 in phosphatides, and at sn2 in both lipid subclasses. Plasmalogens bearing the omega-3 fatty acid docosahexaenoic acid (DHA), a key component of fish oils, are the most abundant plasmalogen species in cerebral cortex membranes.

Circulating plasmalogen levels are decreased in older individuals, and are further decreased in AD and Mild Cognitive Impairment (MCI). In addition, reduced indices of plasmalogen biosynthesis and/or remodeling are significantly correlated with elevated cerebrospinal fluid (CSF) concentrations of total tau, which is a biomarker of AD and certain other neurodegenerative diseases. This correlation suggests a functional relationship between reduced plasmalogen availability and neurodegeneration.

Endogenous plasmalogen synthesis requires the integrity of peroxisomes for the attachment of an alkyl side chain to the sn1 glycerol carbon. Decreased peroxisome function may be a key factor underlying the decrease in circulating plasmalogens with aging and with neurodegenerative diseases such as AD and ADRD.

Preclinical data indicate that oral administration of a precursor phospholipid compound, DHA-containing alkyl-diacylglycerol, or DHA-AAG, can increase circulating DHA-containing plasmalogens in a peroxisome-independent manner, as conversion to plasmalogens from this precursor requires only the endoplasmic reticulum.

We present here data showing that: 1) oral administration of a single dose of DHA-AAG at 100mg/kg to 6 (4M/2F) healthy subjects aged 23-56 increased circulating plasmalogen levels by 80% within 24 hours; and 2) daily oral administration of DHA-AAG to 22 persons (11M/11F), aged 37-84 (mean= 69) yr, with mild to moderate cognitive impairment [CDR: 0.5 (N=14); 1 (N=4); 2 (N = 4)] on an ascending-dose schedule of 1.0 ml/day for 30 days, followed by 2.0 ml/day for 60 days, followed by 4.0 ml for 30 days, increased serum DHA plasmalogens by > 2-fold by the end of the treatment period. DHA-AAG was well-tolerated by both groups of individuals in these 2 studies.

These findings suggest that DHA-AAG may be a useful agent for correcting plasmalogen deficiency associated with aging and aging-associated cognitive disorders. Future studies will examine the effect of plasmalogen repletion with DHA-AAG on cerebrospinal fluid plasmalogen concentrations, and effects on cognitive function and other clinical outcomes.

Keywords

Plasmalogens, Alzheimer Disease, Dementia, Phospholipids, Cognitive Dysfunction

Disciplines

Geriatrics | Medical Neurobiology | Medicine and Health Sciences | Nervous System Diseases | Neurology | Neurosciences | Pathological Conditions, Signs and Symptoms

Document Type

Poster

COinS
 
May 5th, 12:00 AM

Plasmalogen Deficiency: A Risk Factor for Dementias and Potential Treatment Target

Altered lipid metabolism is implicated in the risk of sporadic Alzheimer’s disease (AD) and related dementias (ADRD); however, the precise mechanisms accounting for findings from observational studies remains to be fully elucidated.

Plasmalogens are a subclass of integral membrane phospholipids with unique properties that appear to play important roles relevant to the pathophysiology of AD and ADRD, including vesicle fusion necessary for synaptic neurotransmitter release, modulation of membrane fluidity and microdomain dynamics, membrane antioxidant functions, and neuroprotection. Like the more familiar phosphatides, plasmalogens are synthesized on a 3-carbon glycerol backbone; however, they differ from phosphatides by the presence of a vinyl ether linkage at the 1st (sn1) glycerol carbon atom in place of the acyl ester linkage present at sn1 in phosphatides, and at sn2 in both lipid subclasses. Plasmalogens bearing the omega-3 fatty acid docosahexaenoic acid (DHA), a key component of fish oils, are the most abundant plasmalogen species in cerebral cortex membranes.

Circulating plasmalogen levels are decreased in older individuals, and are further decreased in AD and Mild Cognitive Impairment (MCI). In addition, reduced indices of plasmalogen biosynthesis and/or remodeling are significantly correlated with elevated cerebrospinal fluid (CSF) concentrations of total tau, which is a biomarker of AD and certain other neurodegenerative diseases. This correlation suggests a functional relationship between reduced plasmalogen availability and neurodegeneration.

Endogenous plasmalogen synthesis requires the integrity of peroxisomes for the attachment of an alkyl side chain to the sn1 glycerol carbon. Decreased peroxisome function may be a key factor underlying the decrease in circulating plasmalogens with aging and with neurodegenerative diseases such as AD and ADRD.

Preclinical data indicate that oral administration of a precursor phospholipid compound, DHA-containing alkyl-diacylglycerol, or DHA-AAG, can increase circulating DHA-containing plasmalogens in a peroxisome-independent manner, as conversion to plasmalogens from this precursor requires only the endoplasmic reticulum.

We present here data showing that: 1) oral administration of a single dose of DHA-AAG at 100mg/kg to 6 (4M/2F) healthy subjects aged 23-56 increased circulating plasmalogen levels by 80% within 24 hours; and 2) daily oral administration of DHA-AAG to 22 persons (11M/11F), aged 37-84 (mean= 69) yr, with mild to moderate cognitive impairment [CDR: 0.5 (N=14); 1 (N=4); 2 (N = 4)] on an ascending-dose schedule of 1.0 ml/day for 30 days, followed by 2.0 ml/day for 60 days, followed by 4.0 ml for 30 days, increased serum DHA plasmalogens by > 2-fold by the end of the treatment period. DHA-AAG was well-tolerated by both groups of individuals in these 2 studies.

These findings suggest that DHA-AAG may be a useful agent for correcting plasmalogen deficiency associated with aging and aging-associated cognitive disorders. Future studies will examine the effect of plasmalogen repletion with DHA-AAG on cerebrospinal fluid plasmalogen concentrations, and effects on cognitive function and other clinical outcomes.

 

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