Lipid invasion model: A new theory to explain the pathogenesis of Alzheimer's disease.

Subject

Alzheimer's disease (AD) is caused by several problems in the brain, including the buildup of the protein β‑amyloid (Aβ) and an imbalance in fats (lipids), but it is still unclear exactly how these changes lead to the symptoms of memory loss. Despite much investment in treatments aimed at β‑amyloid, clinical results have been modest, suggesting that other mechanisms are also involved.

The "lipid invasion" model, proposed by Dr. Jonathan Rudge (University of Reading), suggests that when the barrier separating the blood from the brain (the blood-brain barrier, BBB) is damaged, "bad" cholesterol (LDL) and free fatty acids enter the brain more easily. This abnormal entry can alter nerve cell metabolism, increase oxidative stress and inflammation, thus promoting the damage typical of AD. The BBB weakens with age (the main risk factor for the most common form of Alzheimer's) and is further damaged by alcohol, smoking, high blood pressure, head trauma, and certain genetic variants such as APOE. ε4, risk factors for AD.

The hippocampus, a brain region key to memory and spatial orientation, is among the first areas to malfunction in AD, both in people and animal models. However, it's still unclear how risk factors for late-onset AD gradually cause these changes in nerve cells before actual neurodegeneration begins.

The proposed project aims to test the lipid invasion model by combining:

1. studies on mouse brain tissue and human “mini-brains” in the laboratory to see how Aβ and LDL alter the excitability and communication between neurons;
2. analysis of changes in the blood-brain barrier, amyloid proteins, cholesterol, and involved genes.

This study aims to understand whether modifying lipid metabolism and transport can help prevent or slow cognitive decline in AD.

Learning outcomes

To evaluate the effect of lipids on neuronal function in mice and humans.

HYPOTHESIS
1) We hypothesize that LDL cholesterol leads to activation of the amyloidogenic pathway and associated alteration of the neurophysiological and synaptic function of hippocampal CA1 pyramidal neurons.
Pathological levels of LDL cholesterol:

1. will cause synaptic impairment and intrinsic excitability alterations in CA1 pyramidal neurons
2. will increase the processing of Aβ, leading to its accumulation
3. will increase the presence of lipid droplets in glial cells
4. sex-related neurosteroid hormones, 17β-estradiol and testosterone, decrease

2) Similarly, we hypothesize that Aβ accumulation (acute or chronic) causes altered lipid metabolism associated with neuronal dysfunction in CA1 pyramidal neurons.
The APP NLGF knock-in mouse line shows:

1. Accumulation of pathogenic amyloid species at 18–22 months of age in the hippocampus
2. a synaptic alteration and an alteration of intrinsic excitability in CA1 pyramidal cells at 18-22 months of age
3. alterations in the lipidome at 18-22 months of age
4. The same hypotheses tested in ac will be tested in healthy 6-12 week old mice in which brain slices will be incubated for 2-5 hours with β-amyloid protein.

3) Blood markers of dyslipidemia and BBB integrity correlate with neuronal function and cognitive health in Alzheimer's dementia and MCI. The functional alterations observed in murine neurons are replicated in a subsample of human neurons obtained from the blood of San Marino patients, in which circulating CD34+ monocytes are converted into iPSCs and subsequently into telencephalic neurons.

Each hypothesis will be tested over an indicative period of 5 months.