A New Hypothesis for Alzheimer's Disease: The Lipid Invasion Model

Abstract

This paper proposes a new hypothesis for Alzheimer's disease (AD)-the lipid invasion model. It argues that AD results from external influx of free fatty acids (FFAs) and lipid-rich lipoproteins into the brain, following disruption of the blood-brain barrier (BBB). The lipid invasion model explains how the influx of albumin-bound FFAs via a disrupted BBB induces bioenergetic changes and oxidative stress, stimulates microglia-driven neuroinflammation, and causes anterograde amnesia. It also explains how the influx of external lipoproteins, which are much larger and more lipid-rich, especially more cholesterol-rich, than those normally present in the brain, causes endosomal-lysosomal abnormalities and overproduction of the peptide amyloid-β (Aβ). This leads to the formation of amyloid plaques and neurofibrillary tangles, the most well-known hallmarks of AD. The lipid invasion model argues that a key role of the BBB is protecting the brain from external lipid access. It shows how the BBB can be damaged by excess Aβ, as well as by most other known risk factors for AD, including aging, apolipoprotein E4 (APOE4), and lifestyle factors such as hypertension, smoking, obesity, diabetes, chronic sleep deprivation, stress, and head injury. The lipid invasion model gives a new rationale for what we already know about AD, explaining its many associated risk factors and neuropathologies, including some that are less well-accounted for in other explanations of AD. It offers new insights and suggests new ways to prevent, detect, and treat this destructive disease and potentially other neurodegenerative diseases.

Keywords: Alzheimer’s disease; anesthesia; anterograde amnesia; apolipoproteins; blood-brain barrier; cholesterol; ethanol; lipids; lipoproteins; nonesterified fatty acids.

Fig. 1

Comparison of amyloidogenic and non-amyloidogenic processing of AβPP.

Fig. 2

Endosomal-lysosomal pathway and amyloidogenesis (not to scale). Non-amyloidogenic pathway: (a) In phospholipid-rich/cholesterol-poor plasma membrane (PM) regions, AβPP is first preferentially cleaved by α-secretase, then (b) within vesicles by γ-secretase, resulting in the P3 and γCTF peptides. Amyloidogenic pathway: (c) In cholesterol-rich PM regions, AβPP is instead first preferentially cleaved by β-secretase within vesicles, resulting in sAβPPβ and βCTF peptides. (d) Within early/late endosomes βCTF is further cleaved by γ-secretase, (e) resulting in Aβ, as well as γCTF. Normally, such downstream AβPP cleavage products then follow much the same route as cholesterol via late endosomes, (f) lysosomes, (g) the endoplasmic reticulum and/or Golgi apparatus, returning back to the PM. However, excess βCTF levels (resulting from excessive AβPP levels or β-secretase activity, or from downregulated γ-secretase activity) may lead to endosomal-lysosomal pathology (h), characterized by numerous excessively large early endosomes. In the same way, excessive cholesterol uptake may result in a similar pathology, possibly by overstimulating β-secretase activity. (i) This pathway stalling at the early endosome stage appears to result from βCTF-mediated excessive Rab5 activation, involving APPL1 stabilization. (j) Finally, defective NPC1- or NPC2-mediated cholesterol transport may lead to a similar “lipid traffic jam”, this time principally characterized by enlarged late endosomes.

Fig. 3

Summary diagram of lipid invasion model, showing basic differences between normal and AD-affected lipid transport. Diagram does not show bioenergetic changes or GABAergic aspects (tonic inhibition and inhibition of neurogenesis). Figure not to scale.