Molecular and Cellular Models of AD

1. Neuronal ApoE4 and Activated Microglia Co-conspirator Model for Driving the initiation and early progression of AD

Microglia depletion reduces human neuronal APOE4-related pathologies in a chimeric Alzheimer’s disease model – PubMed

Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model | Nature Communications

Depletion of microglia with CSF1R inhibitor prevents tau aggregation in the mouse model Thy1P301S – Lombardo – 2023 – Alzheimer’s & Dementia – Wiley Online Library

Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology | Brain | Oxford Academic

Harnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins: Cell Stem Cell

2. Microglial – Astrocyte Crosstalk Model of AD

Engineered 3D immuno-glial-neurovascular human miBrain model | PNAS

3. Neuron First Model – Premature and halted Neurogenesis regulated by ROS (Reactive Oxygen Species) and altered synaptic protein utilization.

Beta Amyloid Oligomer neurotoxicity by inhibiting the ETC in Neuronal Mitochondria and producing excessive Superoxide Anion

Neuronal Stress Granule Formation — the First Event

Early in AD, neurons form stress granules before overt tau or amyloid pathology. SGs nucleate around RNA-binding proteins such as TIA‑1, G3BP1, and TIAR, which aggregate under oxidative or metabolic stress. These granules sequester mRNAs involved in proteostasis and synaptic function, leading to early translational arrest in neurons.^[58]^[60]^[57]
This neuronal SG formation is linked to the mislocalization of TDP‑43 and other splicing factors, representing one of the first measurable molecular stress responses in pre-tangle neurons.^[61]

Transition to Glial Involvement

As AD progresses, astrocytes also develop stress granules—mainly due to inflammatory and oxidative stress—reflecting their metabolic strain rather than being the initiating site. Microglia, while capable of SG formation, show alterations later and typically in the context of inflammatory activation rather than early degenerative signaling.^[59]^[62]^[63]^[64]

Mechanistic Overview

First stage: Neuronal SG assembly triggered by oxidative, mitochondrial, or ER stress.
Intermediate stage: Astrocytes develop SGs linked to neuroinflammation and secretory dysfunction.
Late stage: Chronic SG persistence contributes to pathological aggregates (e.g., tau–TIA‑1 complexes) that drive neuronal death.^[58]^[59]

In summary:
Neurons are the first cells in Alzheimer’s brains to exhibit stress granule formation and pathological persistence, well before glial SG changes appear. These early SG alterations reflect disrupted RNA metabolism and protein homeostasis preceding visible amyloid or tau pathology.

https://pmc.ncbi.nlm.nih.gov/articles/PMC4256948/

https://pmc.ncbi.nlm.nih.gov/articles/PMC10205695/

https://www.aging-us.com/news-room/Stress-Granules-Control-Alzheimers-Gene-Transcripts-and-Neuronal-Proteostasis

https://www.nature.com/articles/s41593-025-01952-z

https://pubmed.ncbi.nlm.nih.gov/40747577/

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.14555

https://www.sciencedirect.com/science/article/pii/S096999612500155X

https://www.sciencedirect.com/science/article/pii/S0896627324002861

https://blog.cellsignal.com/stress-granules-and-neurodegenerative-diseases

https://www.brightfocus.org/grant/targeting-stress-granule-biology-in-alzheimers-disease/

https://news.uthscsa.edu/targeting-brain-immune-cells-could-restore-alzheimers-related-lipid-imbalance/

https://www.sciencedirect.com/science/article/pii/S0378595522002027

https://pmc.ncbi.nlm.nih.gov/articles/PMC6284765/