Abstract
Compared to the rare familial early onset Alzheimer's disease (AD) that results from gene mutations in AbPP and presenilin-1, the pathogenesis of sporadic AD is much more complex and is believed to result from complex interactions between nutritional, environmental, epigenetic and genetic factors. Among those factors, the presence APOE4 is still the single strongest genetic risk factor for sporadic AD. However, the exact underlying mechanism whereby apoE4 contributes to the pathogenesis of sporadic AD remains unclear. Here, we discuss how altered cholesterol intracellular trafficking as a result of apoE4 might contribute to the development of pathological hallmarks of AD including brain deposition of amyloid beta (Ab), neurofibrillary tangles, and synaptic dysfunction.
Highlights
Alzheimer’s disease (AD), the most common neurodegenerative disorder of old age, is characterized clinically by a progressive decline in cognitive function and pathologically by loss of neurons, disturbed synaptic integrity, and the presence of amyloid plaques composed of amyloid beta (Aβ) protein and neurofibrillary tangles composed of hyperphosphorylated tau [1,2]
The structure and composition of apoEcholesterol in brain parenchyma is not known, it is estimated that apoE-cholesterol synthesized in situ in brain is a discoidal shaped HDL-like particle composed of phospholipids and unesterified cholesterol [20,21]. Such HDL-like apoE-cholesterol supplies the neuronal need of cholesterol via receptor-mediated endocytosis (Figure 1), a process where lipoproteins bound to their receptors are internalized, transported to endolysosomes, hydrolyzed to free cholesterol, and from where free cholesterol is transported to various intracellular compartments (ER, Golgi) or plasma membrane via a mechanism involving the Niemann-Pick type C (NPC) proteins type-1 (NPC1) and -2 (NPC2) proteins [22,23,24]
Brain cholesterol is almost completely dependent on in situ synthesis of HDL-like apoE-cholesterol by astrocytes. Such HDL-like apoE-cholesterol supplies the neuronal need of cholesterol via receptor-mediated endocytosis, a process where apoE-cholesterol bound to their receptors are internalized, transported to endolysosomes, hydrolyzed to free cholesterol, and from where free cholesterol is transported to various intracellular compartments (ER, Golgi) or plasma membrane via a mechanism involving the Niemann-Pick type C proteins type-1 and -2 proteins
Summary
Alzheimer’s disease (AD), the most common neurodegenerative disorder of old age, is characterized clinically by a progressive decline in cognitive function and pathologically by loss of neurons, disturbed synaptic integrity, and the presence of amyloid plaques composed of amyloid beta (Aβ) protein and neurofibrillary tangles composed of hyperphosphorylated tau [1,2]. We discuss how altered cholesterol intracellular trafficking as a result of apoE4 might contribute to the development of pathological hallmarks of AD including brain deposition of Aβ, neurofibrillary tangles, and synaptic dysfunction.
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