Alexei R. Koudinov

Cholesterol homeostasis failure as a unifying cause of synaptic degeneration

We previously showed that fine tuning of neural cholesterol dynamics is essential for basic synapse function, plasticity and behavior. Significant experimental evidence indicates that cholinergic function, ionotropic and metabotropic receptor machinery, excessive tau phosphorylation, the change of amyloid beta (Abeta or Abeta) biochemistry, neural oxidative stress reactions, and other features of neurodegeneration also depend on fine tuning of brain cholesterol homeostasis. This evidence suggest that (i) cholesterol homeostasis break is the unifying primary cause of sporadic and familial Alzheimers disease (AD), neuromuscular diseases (particularly inclusion-body myositis), Niemann-Picks type C disease and Down syndrome, and (ii) explains the overlap of neurodegenerative hallmarks across the spectrum of neurodegenerative diseases. Provided is evidence-based explanation of why extremely rare (but scientifically popular) cases of AD associated with mutations in amyloid beta protein precursor (APP) and presenilin (PS) genes, are translated into the disorder via membrane cholesterol sensitivity of APP processing by secretases and Abeta generation. The reciprocal effect of Abeta on cholesterol synthesis, cellular uptake, efflux and esterification is summarized, as well as the potential implication of such biological function for the compensatory Abeta-assisted restoration of the synaptic long-term potentiation (LTP) and resulting inability of tackling amyloid to cure AD.

Alzheimer's amyloid β interaction with normal human plasma high density lipoprotein : Association with apolipoprotein and lipids

We report studies of the interaction of Alzheimers amyloid beta protein (A beta) with normal human plasma high density lipoprotein (HDL), aiming to clarify to which lipoprotein (LP) structural constituent (apolipoprotein or lipid) soluble A beta is primarily bound. Purified HDLs were incubated with biotinylated A beta 1-40 followed by LP repurification by size exclusion (SE) HPLC. SDS-PAGE, immunoblot and N-terminal sequence analysis of the biotin-A beta positive protein bands revealed that A beta is bound to many apolipoproteins of the HDL, mainly apoA-I, apoA-II, apoE and apoJ. On the other hand, reconstituted, protein-free HDL lipid particles also bind A beta peptide and inhibit its aggregation, as intact HDL does. This was assessed by SE-HPLC, SDS-PAGE, immunoblot analysis, ultrastructural electron microscopy and Congo Red staining for beta amyloid fibrils. Our data imply that A beta binding to lipids may play an important role in maintaining the peptide in solution and thus be particularly relevant to A beta normal and pathologic biochemistry and physiology.

The levels of soluble amyloid beta in different high density lipoprotein subfractions distinguish Alzheimer's and normal aging cerebrospinal fluid: implication for brain cholesterol pathology?

Several previous studies reported the association of the soluble form of amyloid beta (sA beta) protein, a major constituent of amyloid deposits in Alzheimers disease (AD), with normal blood, cerebrospinal fluid (CSF) and central nervous system high density lipoproteins (HDLs). The present report aimed to elucidate the pattern of sA beta and apolipoprotein (apo) distribution in AD CSF-HDL subfractions. We studied AD CSF-HDL subfractions by SDS/PAGE and immunoblot analysis after CSF fractionation via density flotation ultracentrifugation. AD CSF was characterized by (i) increased sA beta and apo content of the HDL(1), and (ii) sA beta association with apoE and apoJ in HDL(2), HDL(3) and very high density lipoproteins. The finding supports our proposed hypothesis that upregulation of brain cholesterol dynamics is a fundamental event in the pathophysiology of AD and that sA beta binding to apo and lipid may have important structure-functional consequences.

Multiple inhibitory effects of Alzheimer's peptide Aβ1–40 on lipid biosynthesis in cultured human HepG2 cells

Herein we describe the inhibitory effect of the synthetic peptide Aβ1–40, homologous to the major high‐density lipoprotein‐associated species of Alzheimers amyloid β protein (Aβ), on lipid biosynthesis in human hepatic HepG2 cells. This culture synthesizes various lipids from [14C]acetate as a precursor. Treatment of cells with different concentrations of Aβ1–40 decreased the syntheses of various radiolabeled lipid species. The decrease reached saturation at peptide concentrations equal to 10–100 ng ml−1. The lipids whose synthesis was decreased most were free and esterified cholesterol and phospholipids. This inhibitory effect suggests that Aβ protein may modulate physiological intracellular lipid syntheses. It may also be of special importance in the pathological condition, and contribute to the neurodegeneration, in Alzheimers disease and related disorders.

[Amyloid beta: functional protein or biological junk?].

During a decade there was a dogma that Alzheimer’s amyloid beta (Aβ) is produced only upon the disease, and that this protein is neurotoxic for neurons and brain tissue. Current scientific evidence demonstrates that Aβ is an essential molecule in synaptic plasticity that underlines learning and memory. Therefore, it was hypothesized that the change of Aβ biology in Alzheimer’s disease (as well as in a number of other human pathologies, including cardiovascular disease, Niemann-Pick type C disease and Down syndrome) represents a physiological mechanism serving to compensate the impaired brain structure or function. This review summarizes experimental evidence on Aβ as a functional player in synaptic plasticity and neurochemical pathways.

Compensatory mechanisms to heal neuroplasticity impairment under Alzheiemr’s disease neurodegeneration. I: The role of amyloid beta and its’ precursor protein

In-depth scholar literature analysis of Alzheimer’s disease neurodegenerative features of amyloid beta protein neurochemistry modification and excessive phosphorylation of tau protein (and associated neuronal cytoskeleton rearrangements) are secondary phenomena. At early disease stage these neurobiochemical mechanisms are reversible and serve to heal an impairment of biophysical properties of neuronal membranes, neurotransmission, basic neuronal function and neuroplasticity, while preserving anatomical and functional brain fields. Aβ and tau could well serve to biochemically restore physico-chemical properties of neual membranes due to a role these proteins play in lipid metabolism. Under such scenario therapeutic block of aggregation and plaque formation of Aβ and inhibition of tau phosphorylation, as well as pharmaceutical modification of other secondary neurodegenerative features (such as a cascade of oxidative stress reactions) are unable to provide an effective cure of Alzheimer’s disease and related pathologies of the Central and peripheral nervous systems, because they are not arraying primary pathagenetic cause. We review the role of Aβ in compensatory mechanisms of neuroplasticity restoration under normal physiological condition and Alzheimer’s disease.