Different Cellular Mechanisms in Familial and Sporadic Alzheimer’s?

How alike are familial and sporadic Alzheimer’s? It depends. Broadly speaking, in terms of their presymptomatic biomarker changes, the two resemble each other closely (see Feb 2024 news). In terms of what goes on inside affected cells, things look more diverse. In the February 27 Neuron, researchers led by Kenneth Kosik at the University of California, Santa Barbara, report different cellular manifestations of disease.

  • Neurons and astrocytes carrying the Paisa presenilin mutation rev up chaperones and autophagy.
  • Paisa microglia are less activated than sporadic AD microglia.
  • The protective Christchurch mutation dials up genes that may prevent tangles.

Using single-nuclei RNA-Seq, the authors compared gene expression in the postmortem frontal cortices of sporadic and familial AD brains, the latter coming from the Colombian kindred that carries the Paisa E280A mutation in presenilin 1. While most changes were common to familial and sporadic disease, the authors also found subtle differences. For example, chaperones and protein degradation genes were expressed more in Paisa brains, while microglia were more activated in sporadic AD. The data suggest there could be distinct mechanisms at work, hinting at the potential for tailoring therapies to each form of AD, Kosik noted.

The authors also examined postmortem brain samples from Aliria Rosa Piedrahita de Villegas, who carried both the Paisa presenilin mutation and two copies of the protective Christchurch APOE mutation. She had remained cognitively healthy 20 years past this mutation's typical age at onset. Several changes popped up, including more neuronal FKBP12 and astrocytic LRP1—clues to her brain’s extraordinary resistance to tau pathology.

Christchurch Astros. In autosomal-dominant AD brain, astrocytes (green) with the protective Christchurch APOE mutation (left) express receptor LRP1 (red; overlay looks gold); this may help them take up aggregated tau. Astrocytes without the Christchurch mutation (right) do not. Nuclei are blue. [Courtesy of Almeida et al., Neuron.]

Kosik has studied the Colombian kindred for more than 30 years, collaborating with Francisco Lopera at the Universidad de Antioquia, Medellin, a co-author on the current paper. For this study, joint first authors Maria Almeida and Sarah Eger analyzed frontal cortex samples from 10 Paisa carriers with AD, eight noncarriers from the same kindred, and eight unrelated people with sporadic AD. Altogether, they analyzed 55,000 nuclei and 2,074 genes per nucleus.

The comparison turned up differences between familial and sporadic disease, with a few hundred discordant genes per cell type. Both neurons and astrocytes of Paisa brains expressed more chaperone and autophagy genes than did these cells in sporadic AD brains. The upregulation might represent compensation as chaperones help fold mutant presenilin, the authors suggested.

A set of 45 genes that regulate Aβ production and secretion were turned up or down in Paisa neurons, oligodendrocytes, and microglia, more than they were in sporadic AD, perhaps as a response to Aβ overproduction. This set, originally analyzed in fresh cortical biopsies from aged hydrocephalus patients who had Aβ pathology, included secretases, other proteases, and Aβ transport proteins (Jul 2023 news).

Meanwhile, in sporadic AD brains, microglia took on a sharper human AD microglia (HAM) profile than did microglia in Paisa brains, perhaps suggesting a larger role for inflammation in late-onset disease (May 2019 news). In addition, interneurons expressing PROX1 disappeared, again as previously shown in human cortex biopsies. This neuronal subtype was preserved in Paisa brains. Both sporadic and ADAD brains lost RORB-positive excitatory neurons, which were reported to be vulnerable to tau toxicity (Jan 2021 news).

The Christchurch brain samples offered clues to how resilience might work. Despite having ample amyloid, Piedrahita de Villegas had developed almost no tau tangles and little cognitive impairment in her life, and maintained her RORB neurons (Nov 2019 news; Sep 2022 news).

In her frontal cortex, the authors spotted several intriguing changes. Excitatory neurons made more of the chaperone FKBP12, and less FKBP51, than did Paisa PS1 neurons from people without the Christchurch variant; FKBP12 has been shown to curb tangles, while FKBP51 promotes them (Feb 2023 news; Sep 2013 news). Together, these changes might lessen tau pathology. Her excitatory neurons also made more of the protective retromer gene VPS35, and less presenilin 1, potentially suppressing Aβ production.

In Piedrahita de Villegas' astrocytes, lipid metabolism was revved up compared to that in astrocytes from other Paisa carriers. Glial lipid metabolism falters in AD (Apr 2019 conference news; Aug 2019 news; Nov 2021 news).

Her astrocytes also made more LRP1, aka LDL-receptor-related protein 1. The Kosik lab had previously reported that this cell-surface receptor binds tau, perhaps helping tangles spread from cell to cell (Mar 2020 conference news). Why, then, would more of it be protective? Astrocytes flush with LRP1 took up paired helical filaments of tau, as seen by AT8 antibody binding. Possibly, LRP1 enables these cells to clear pathologic tau, the authors speculated. Supporting this, in the occipital cortex, the one area of Piedrahita de Villegas's brain that did accumulate tangles, astrocytes had not dialed up LRP1 expression. Neuronal LRP1 remained low throughout her brain.

“To me, the LRP1 findings are the most provocative part of the paper,” Kosik told Alzforum. “It suggests upregulating LRP1 in astrocytes may be a good thing.” He is testing this idea in cultured astrocytes made from iPS cells carrying the Christchurch mutation.—Madolyn Bowman Rogers

Comments

    • User Profile Image Guojun Bu
      Hong Kong University of Science & Technology
    • Posted:

    The increased level of LRP1 in astrocytes observed in this study is quite interesting. It could be a contributing mechanism of protection by the APOE Christchurch variant. Other mechanisms could include reduced binding to HSPG and other apoE receptors such as LRP1.

    While this type of study is informative, it’s overall suggestive and will need functional studies to clarify its relevance to the protective mechanism in disease models.

    View all comments by Guojun Bu

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References

News Citations

  1. From St. Louis to Beijing: AD Biomarkers Change Similarly Before Symptoms
  2. Cortical Biopsies Hint at Start of Alzheimer's 'Cellular Phase'
  3. When It Comes to Alzheimer’s Disease, Do Human Microglia Even Give a DAM?
  4. Selective Vulnerability News: RORB Neurons Are First Victims of Tangles
  5. Can an ApoE Mutation Halt Alzheimer’s Disease?
  6. In Brain With Christchurch Mutation, More ApoE3 Means Fewer Tangles
  7. The Chaperone FKBP12 Shields Tau from Aggregation
  8. Chaperone “Saves” Tau, Turning it into Toxic Oligomers
  9. Could Greasing the Wheels of Lipid Processing Treat Alzheimer’s?
  10. ApoE4 Glia Bungle Lipid Processing, Mess with the Matrisome
  11. Do Lipids Lubricate ApoE's Part in Alzheimer Mechanisms?
  12. Tau Receptor Identified on Cell Surface

Mutations Citations

  1. PSEN1 E280A (Paisa)
  2. APOE R154S (Christchurch)

Further Reading

Primary Papers

  1. Almeida MC, Eger SJ, He C, Audouard M, Nikitina A, Glasauer SM, Han D, Mejía-Cupajita B, Acosta-Uribe J, Villalba-Moreno ND, Littau JL, Elcheikhali M, Rivera EK, Carrettiero DC, Villegas-Lanau CA, Sepulveda-Falla D, Lopera F, Kosik KS. Single-nucleus RNA sequencing demonstrates an autosomal dominant Alzheimer's disease profile and possible mechanisms of disease protection. Neuron. 2024 Jun 5;112(11):1778-1794.e7. Epub 2024 Feb 27 PubMed.

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