Taking certain hypertension medications has been linked to a lower risk of Alzheimer’s disease—but does that happen via lower blood pressure, or some other way? In the September 30 Science Translational Medicine, researchers led by Robert Vassar at Northwestern University in Chicago and Rudolph Tanzi at Massachusetts General Hospital, Boston, provide evidence for the latter. They identified a rare genetic variant in the blood-pressure gene angiotensin-converting enzyme (ACE) that associated with AD. Surprisingly, the variant did not affect blood pressure in a knock-in mouse model. Instead, it accumulated on neuronal cell membranes, killing off hippocampal neurons as the mice aged. Females fared worse, developing neuroinflammation and memory problems as well. Treating the mice with medications that block ACE1 or its receptor prevented the deficits.
- A rare coding variant in ACE boosts protein levels and associates with AD.
- Knock-in mice lose hippocampal neurons as they age, and females develop neuroinflammation.
- The variant worsens degeneration in a mouse model of amyloidosis.
Vassar believes the data delineate another pathway involved in AD degeneration, separate from amyloid and tau, that explains some of the characteristics of the disease. “Our study gives us some insight into three of the mysteries of Alzheimer’s: why is age the primary risk factor, why do women have increased susceptibility, and why is there selective neuron loss in the hippocampus?” Vassar told Alzforum.
Giulio Pasinetti at the Icahn School of Medicine at Mount Sinai, New York, appreciated the therapeutic implications. “This is an excellent paper, showing a potential pathogenic mechanism by which ACE might increase the odds of developing AD … [it] provides a rationale for repurposing ACE inhibitors,” Pasinetti wrote to Alzforum (full comment below).
Neuronal Apocalypse. By 14 months of age, mice carrying one copy of the ACE R1284Q variant (middle) have lost more neurons (red) than controls (left), while mice homozygous for the variant (right) have lost far more. [Courtesy of Cuddy et al., Science Translational Medicine.]
Pasinetti had previously reported that an angiotensin receptor blocker (ARB), a common blood pressure medication, improved memory and cut plaque load in a mouse model of amyloidosis (Oct 2007 news). In people, an epidemiological study of 800,000 veterans linked ACE inhibitors and ARBs to a lower risk of dementia (Jan 2010 news). ARBs also associated with lower plaque load in cognitively impaired people (Sep 2012 news).
Supporting this epidemiologic data, genome-wide association studies recently pegged ACE as an AD risk gene (Apr 2018 news; Kunkle et al., 2019; Jansen et al., 2019). In particular, an insertion in the noncoding region of ACE that boosts expression associates with a higher AD risk in women (Sleegers et al., 2005).
Vassar and colleagues searched for additional risk variants in ACE by analyzing whole-genome sequencing from 446 families in the National Institute of Mental Health AD Genetics Initiative Study Sample. In seven families, they found a coding variant, R1279Q, that associated with AD, with nine of 11 carriers having the disease. Additional analysis of the National Institute on Aging family dataset confirmed the association.
First author Leah Cuddy generated a knock-in mouse that expressed the homologous ACE variant, R1284Q. Immunostaining revealed these knock-ins had more ACE1 protein in their brains than did wild-type. The protein co-localized with neuronal, but not microglial or astrocyte markers, suggesting it is exclusively expressed in neurons.
In both knock-ins and wild-types, ACE1 levels rose with age. This increase was most pronounced in females. ACE1 cleaves angiotensin I to angiotensin II, which hikes blood pressure. While knock-ins had more angiotensin II in their brains than did wild-types, curiously, their blood pressure was normal.
What might ACE1 be doing in the brain? At 8 months old, knock-ins and wild-types had no obvious brain differences. But by 14 months, both male and female knock-ins had smaller hippocampi, striata, and amygdalae than controls, indicative of atrophy. In vitro studies strengthened this association. Cultured forebrain neurons isolated from the knock-ins were more prone to apoptosis than were their wild-type counterparts.
Female knock-ins fared worse than male. In addition to hippocampal atrophy, they developed neuroinflammation, with larger numbers of activated microglia and astrocytes than in the hippocampi of controls. They lost hippocampal synapses, as seen by a drop in the presynaptic marker synaptophysin, and performed poorly in fear-conditioning tests and the Morris water maze. Their sleep rhythms were off, with higher alpha and theta power in the hippocampus. Disrupted theta rhythms have been linked to AD and memory problems (Aug 2010 news; Mar 2020 news).
It is unclear how the ACE1 variant does this. In cultured knock-in neurons, more of the protein accumulated on the cell surface, and less was shed into the media than in wild-type cultures. Vassar believes the variant decreases cleavage of cell-surface ACE1, rather than affecting expression directly. Either way, the high levels of exposed ACE1 produced more angiotensin II, which bound to its receptor AT1R on neurons. That triggered phosphorylation of the kinase Erk, activating downstream pathways implicated in autophagy, aging, and AD. Vassar thinks this signaling may be the source of neurotoxicity. Hippocampal neurons express higher levels of AT1R than those in other brain regions, and R1284Q ACE1 knock-ins had about 50 percent more phospho-Erk in hippocampus than did controls.
Microglia also express AT1R, and its activation stimulates proinflammatory signaling (Labandeira-Garcia et al., 2017). Intriguingly, some prior research has found that microglia in female mice are more prone to inflammation than those in males, hinting at a possible mechanism for the gender difference in the knock-ins (Jul 2019 conference news).
To the Rescue. Neurons (red) pack the hippocampus of an aged wild-type mouse (far left), die off in an ACE R1284Q knock-in mouse (left), but are preserved in knock-ins treated with an ACE inhibitor (right) or ARB (far right). [Courtesy of Cuddy et al., Science Translational Medicine.]
If angiotensin II causes toxicity, could inhibiting it preserve neurons? To test this, the authors treated R1284Q ACE1 knock-in and wild-type mice with either the ACE1 inhibitor captopril or the AT1R blocker losartan from 9 to 15 months of age. Both drugs prevented hippocampal atrophy, and in females, squelched neuroinflammation as well (see image above). The authors are currently testing memory in the treated mice.
How does this pathway relate to Alzheimer’s disease? The authors crossed the knock-ins with 5XFAD mice and evaluated their brains at 6 months. ACE1 has been reported to degrade Aβ in vitro, but in contrast to some previous mouse studies of angiotensin receptor blockers, the authors found no difference in plaque load in 5XFAD mice carrying the ACE1 variant (Oct 2005 news). However, the variant accelerated hippocampal atrophy in all 5XFAD mice and, in females, activated microglia more. To Vassar, this suggests a two-hit hypothesis. “Maybe ACE1 increasing with age, together with amyloid buildup, combines to trigger neuroinflammation and degeneration,” he suggested.
Edo Richard at Radboud University Medical Centre, Nijmegen, The Netherlands, noted that it remains unclear how hypertension contributes to neurodegeneration. “[These data] may provide an important lead for future research aiming to bridge the knowledge gap spanning links among blood pressure, antihypertensive medication, neurodegeneration and dementia,” he wrote to Alzforum (full comment below).
To find out if their findings might be relevant to people, the authors examined postmortem cortical and hippocampal sections from seven AD and 13 age-matched control brains. They found higher levels of ACE1 in AD cortex, as well as fewer ACE1-positive neurons in AD hippocampus. The data suggest angiotensin II signaling could play a role in AD even in the absence of an ACE1 mutation, Vassar said.
Vassar believes it would be worth testing brain-penetrant ACE inhibitors and ARBs in people with preclinical AD. In this case, the human equivalent of the ACE inhibitor and ARB doses used in the mouse studies would be twice the maximum prescribed for hypertension. The authors have not yet tested if lower doses could be effective. Because these drugs lower blood pressure, it might be necessary to titrate up dosage in people with normal blood pressure, Vassar noted. In a prevention paradigm, he believes lower doses might be sufficient. If they work, they could eventually be combined with treatments that target amyloid or tau, he suggested.
Richard agreed. “Using specific antihypertensive drugs in selected populations as one of several approaches may contribute to the prevention of cognitive decline and dementia. Future clinical studies should provide further evidence on whether such an approach is viable,” Richard wrote. Drug repurposing is often attempted in Alzheimer’s disease and many other areas of medical research, but rarely successful (e.g., Nov 2019 news; saracatinib; or, most recently Edwards 2020). In an unrelated note, the new SARS-CoV-2 virus spike protein binds ACE-2.—Madolyn Bowman Rogers
- Anti-hypertensives for AD?—Remembrances of NSAIDs Past
- In Veterans, Blood Pressure Meds Delay Dementia
- Can Blood Pressure Drug Put the Squeeze on Brain Amyloid?
- GWAS, GWAX: bioRχiv Hosts Bonanza of Alzheimer’s Genetics
- Off Key—Aβ Detunes the Theta Rhythms of the Hippocampus
- Plaques, Tangles Throw Off the Brain’s Rhythms
- Down to Sex? Boy and Girl Microglia Respond Differently
- We Are What We Consume? Foods, Drugs Affect Amyloid, AD
- Minocycline Does Not Work in Mild Alzheimer’s Disease
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