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Cholesterol homeostasis: a key to prevent or slow down neurodegeneration.

Anchisi L, Dessì S, Pani A, Mandas A - Front Physiol (2013)

Bottom Line: Typically human neurodegenerative diseases are devastating illnesses that predominantly affect elderly people, progress slowly, and lead to disability and premature death; however they may occur at all ages.Therefore, since the underlying mechanisms of damage to neurons are similar, in spite of etiology and background heterogeneous, it will be of interest to identify possible trigger point of neurodegeneration enabling development of drugs and/or prevention strategies that target many disorders simultaneously.Among the factors that have been identified so far to cause neurodegeneration, failures in cholesterol homeostasis are indubitably the best investigated.

View Article: PubMed Central - PubMed

Affiliation: Child Neuropsychiatry Unit, Azienda Sanitaria Locale (ASL) n°5 Oristano, Italy ; Department of Clinical and Experimental Medicine and Pharmacology, University of Messina Messina, Italy.

ABSTRACT
Neurodegeneration, a common feature for many brain disorders, has severe consequences on the mental and physical health of an individual. Typically human neurodegenerative diseases are devastating illnesses that predominantly affect elderly people, progress slowly, and lead to disability and premature death; however they may occur at all ages. Despite extensive research and investments, current therapeutic interventions against these disorders treat solely the symptoms. Therefore, since the underlying mechanisms of damage to neurons are similar, in spite of etiology and background heterogeneous, it will be of interest to identify possible trigger point of neurodegeneration enabling development of drugs and/or prevention strategies that target many disorders simultaneously. Among the factors that have been identified so far to cause neurodegeneration, failures in cholesterol homeostasis are indubitably the best investigated. The aim of this review is to critically discuss some of the main results reported in the recent years in this field mainly focusing on the mechanisms that, by recovering perturbations of cholesterol homeostasis in neuronal cells, may correct clinically relevant features occurring in different neurodegenerative disorders and, in this regard, also debate the current potential therapeutic interventions.

No MeSH data available.


Related in: MedlinePlus

Alzheimer's disease (AD). AD is a progressive neurologic disease of the brain leading to the irreversible loss of neurons and the loss of intellectual abilities, including memory, and reasoning, which become severe enough to impede social or occupational functioning. Although scientists are still trying to fully understand the cause/s of AD, the formation of amyloid β (Aβ) protein positive neuritic plaques is considered one of the most important characteristic of AD so much so that Aβ deposition in the brain is used to diagnose the disease in autopsy. Aβ peptides are fragments from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane. They are generated in the amyloidogenic pathway (B) of APP processing by sequential proteolysis by β- (BACE1) and γ-secretases. In the alternative non-amyloidogenic APP processing pathway (A), α-secretase cleaves within the Aβ peptide region and prevents Aβ generation.
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Figure 1: Alzheimer's disease (AD). AD is a progressive neurologic disease of the brain leading to the irreversible loss of neurons and the loss of intellectual abilities, including memory, and reasoning, which become severe enough to impede social or occupational functioning. Although scientists are still trying to fully understand the cause/s of AD, the formation of amyloid β (Aβ) protein positive neuritic plaques is considered one of the most important characteristic of AD so much so that Aβ deposition in the brain is used to diagnose the disease in autopsy. Aβ peptides are fragments from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane. They are generated in the amyloidogenic pathway (B) of APP processing by sequential proteolysis by β- (BACE1) and γ-secretases. In the alternative non-amyloidogenic APP processing pathway (A), α-secretase cleaves within the Aβ peptide region and prevents Aβ generation.

Mentions: Growing evidence indicates that membrane lipid rafts are involved in the generation of Aβ and PrPsc amyloidogenic-peptides from amyloid precursor protein (APP) and cellular prion protein (PrPc), (deposition of which in brain parenchyma and vessel walls are the major pathological feature of AD and PrD, respectively), possibly through the creation of a favorable lipid environment (Figures 1 and 2) (Pani et al., 2011). It has been reported that, when APP and PrPc molecules occupy a lipid raft region of the membrane, they are more accessible to and, thus, preferentially cleaved by amyloidogenic enzymes (i.e., raft resident β-secretase or BACE1). On the other hand, when APP and PrPc molecules are outside rafts, they appear to be preferentially cleaved by non-amyloidogenic non-raft resident α-secretase (ADAM 10) (Simons and Ikonen, 1997). It has been thus suggested that APP and PrPc in the brain are present in two cellular pools: one, outside rafts, where these two proteins are processed in a normal way; the other, inside the rafts, where abnormal cleavage takes place (Simons and Ikonen, 1997). If it is so, it can be assumed that compartmentalization of membrane proteins depends by spatial distribution of the lipid raft microdomains which in turn is regulated by the levels of FC and therefore that maintenance of cholesterol homeostasis is essential for neurons. If cholesterol levels are higher or lower than the physiological range; several metabolic pathways of compensation can be activated that if continued for long periods can lead to neurodegeneration through different mechanisms.


Cholesterol homeostasis: a key to prevent or slow down neurodegeneration.

Anchisi L, Dessì S, Pani A, Mandas A - Front Physiol (2013)

Alzheimer's disease (AD). AD is a progressive neurologic disease of the brain leading to the irreversible loss of neurons and the loss of intellectual abilities, including memory, and reasoning, which become severe enough to impede social or occupational functioning. Although scientists are still trying to fully understand the cause/s of AD, the formation of amyloid β (Aβ) protein positive neuritic plaques is considered one of the most important characteristic of AD so much so that Aβ deposition in the brain is used to diagnose the disease in autopsy. Aβ peptides are fragments from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane. They are generated in the amyloidogenic pathway (B) of APP processing by sequential proteolysis by β- (BACE1) and γ-secretases. In the alternative non-amyloidogenic APP processing pathway (A), α-secretase cleaves within the Aβ peptide region and prevents Aβ generation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3539713&req=5

Figure 1: Alzheimer's disease (AD). AD is a progressive neurologic disease of the brain leading to the irreversible loss of neurons and the loss of intellectual abilities, including memory, and reasoning, which become severe enough to impede social or occupational functioning. Although scientists are still trying to fully understand the cause/s of AD, the formation of amyloid β (Aβ) protein positive neuritic plaques is considered one of the most important characteristic of AD so much so that Aβ deposition in the brain is used to diagnose the disease in autopsy. Aβ peptides are fragments from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane. They are generated in the amyloidogenic pathway (B) of APP processing by sequential proteolysis by β- (BACE1) and γ-secretases. In the alternative non-amyloidogenic APP processing pathway (A), α-secretase cleaves within the Aβ peptide region and prevents Aβ generation.
Mentions: Growing evidence indicates that membrane lipid rafts are involved in the generation of Aβ and PrPsc amyloidogenic-peptides from amyloid precursor protein (APP) and cellular prion protein (PrPc), (deposition of which in brain parenchyma and vessel walls are the major pathological feature of AD and PrD, respectively), possibly through the creation of a favorable lipid environment (Figures 1 and 2) (Pani et al., 2011). It has been reported that, when APP and PrPc molecules occupy a lipid raft region of the membrane, they are more accessible to and, thus, preferentially cleaved by amyloidogenic enzymes (i.e., raft resident β-secretase or BACE1). On the other hand, when APP and PrPc molecules are outside rafts, they appear to be preferentially cleaved by non-amyloidogenic non-raft resident α-secretase (ADAM 10) (Simons and Ikonen, 1997). It has been thus suggested that APP and PrPc in the brain are present in two cellular pools: one, outside rafts, where these two proteins are processed in a normal way; the other, inside the rafts, where abnormal cleavage takes place (Simons and Ikonen, 1997). If it is so, it can be assumed that compartmentalization of membrane proteins depends by spatial distribution of the lipid raft microdomains which in turn is regulated by the levels of FC and therefore that maintenance of cholesterol homeostasis is essential for neurons. If cholesterol levels are higher or lower than the physiological range; several metabolic pathways of compensation can be activated that if continued for long periods can lead to neurodegeneration through different mechanisms.

Bottom Line: Typically human neurodegenerative diseases are devastating illnesses that predominantly affect elderly people, progress slowly, and lead to disability and premature death; however they may occur at all ages.Therefore, since the underlying mechanisms of damage to neurons are similar, in spite of etiology and background heterogeneous, it will be of interest to identify possible trigger point of neurodegeneration enabling development of drugs and/or prevention strategies that target many disorders simultaneously.Among the factors that have been identified so far to cause neurodegeneration, failures in cholesterol homeostasis are indubitably the best investigated.

View Article: PubMed Central - PubMed

Affiliation: Child Neuropsychiatry Unit, Azienda Sanitaria Locale (ASL) n°5 Oristano, Italy ; Department of Clinical and Experimental Medicine and Pharmacology, University of Messina Messina, Italy.

ABSTRACT
Neurodegeneration, a common feature for many brain disorders, has severe consequences on the mental and physical health of an individual. Typically human neurodegenerative diseases are devastating illnesses that predominantly affect elderly people, progress slowly, and lead to disability and premature death; however they may occur at all ages. Despite extensive research and investments, current therapeutic interventions against these disorders treat solely the symptoms. Therefore, since the underlying mechanisms of damage to neurons are similar, in spite of etiology and background heterogeneous, it will be of interest to identify possible trigger point of neurodegeneration enabling development of drugs and/or prevention strategies that target many disorders simultaneously. Among the factors that have been identified so far to cause neurodegeneration, failures in cholesterol homeostasis are indubitably the best investigated. The aim of this review is to critically discuss some of the main results reported in the recent years in this field mainly focusing on the mechanisms that, by recovering perturbations of cholesterol homeostasis in neuronal cells, may correct clinically relevant features occurring in different neurodegenerative disorders and, in this regard, also debate the current potential therapeutic interventions.

No MeSH data available.


Related in: MedlinePlus