Experts estimate more than 6 million Americans are living with Alzheimer’s dementia. But a recent study, led by the University of Cincinnati, sheds new light on the disease and a highly debated new drug therapy.
The UC-led study, conducted in collaboration with the Karolinska Institute in Sweden, claims that the treatment of Alzheimer’s disease might lie in normalizing the levels of a specific brain protein called amyloid-beta peptide.
This protein is needed in its original, soluble form to keep the brain healthy, but sometimes it hardens into “brain stones” or clumps, called amyloid plaques.
The study, which appears in the journal EClinicalMedicine (published by The Lancet), comes on the heels of the FDA’s conditional approval of a new medicine, aducanumab, that treats the amyloid plaques.
“It’s not the plaques that are causing impaired cognition,” says Alberto Espay, the new study’s senior author and professor of neurology at UC. “Amyloid plaques are a consequence, not a cause,” of Alzheimer’s disease, says Espay, who is also a member of the UC Gardner Neuroscience Institute.
Alzheimer’s disease became widely known as “the long goodbye” in the late 20th century due to the disease’s slow deterioration of brain function and memory. It was over 100 years ago, however, that scientist Alois Alzheimer first identified plaques in the brain of patients suffering from the disease.
Since then, Espay says that scientists have focused on treatments to eliminate the plaques. But the UC team, he says, saw it differently: Cognitive impairment could be due to a decline in soluble amyloid-beta peptide instead of the corresponding accumulation of amyloid plaques.
From there, they compared the amount of plaques and levels of the peptide in the individuals with normal cognition to those with cognitive impairment. They found that, regardless of the amount of plaques in the brain, the individuals with high levels of the peptide were cognitively normal.
They also found that higher levels of soluble amyloid-beta peptide were associated with a larger hippocampus, the area of the brain most important for memory.
According to the authors, as we age most people develop amyloid plaques, but few people develop dementia. In fact, by the age of 85, 60% of people will have these plaques, but only 10% develop dementia, they say.
“The key discovery from our analysis is that Alzheimer’s disease symptoms seem dependent on the depletion of the normal protein, which is in a soluble state, instead of when it aggregates into plaques,” says co-author Kariem Ezzat from the Karolinska Institute.
The research team is now working to test their findings in animal models. If successful, future treatments may be very different from those tried over the last two decades. Treatment, says Espay, may consist of increasing the soluble version of the protein in a manner that keeps the brain healthy while preventing the protein from hardening into plaques.
Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder, characterized by progressive and irreversible loss of memory. AD is the leading cause of senile dementia. The number of people age 65 and older living with AD’s dementia in the United States is projected to grow from 5.8 million in 2020 to 13.8 million by 2050 (Alzheimer’s_Association, 2020).
Cognitive deficits caused by AD, such as progressive memory loss, difficulty in communication and movement disorder, significantly compromise the patients’ quality of life, leading to hospitalization and eventually death due to complications. AD has been recognized as one of the most difficult medical problems with hefty economic burden (Wimo et al., 2010). Total medical expenses for Alzheimer’s or other dementias in the United States are projected to be $305 billion in 2020 (Alzheimer’s_Association, 2020).
The cost of AD is likely to skyrocket in the near future, due to rising ageing population, increasing mortality relative to other disease and the absence of a disease-modifying drug. Therefore, there is a major unmet medical need for disease-modifying therapies for AD.
Approved drugs for AD include acetylcholinesterase inhibitors (Aricept®, Exelon®, Razadyne®) and NMDA-antagonist memantine (Namenda®). However, these drugs are not disease-modifying, only improving symptoms without slowing down or stopping AD from progressing. In the last 30 years, a large number of drug candidates have entered clinical development but no new drug for AD has been approved since memantine in 2003. The majority of AD drug discovery focused on inhibiting the amyloid-β peptide (Aβ) production from the amyloidogenic processing of APP.
Amyloid Cascade Hypothesis and Amyloidogenic Processing of APP
In the past 30 years, the amyloid hypothesis has been extensively tested and amyloid has been the most compelling therapeutic target for AD. Despite ongoing debates about this hypothesis in light of recent failures of anti-amyloid-based clinical trials, new evidences continue to emerge to support the idea that an imbalance between production and clearance of Aβ peptides is the initiating event of AD pathogenic processes.
Abnormal accumulation of amyloid eventually leads to formation of senile plaques and neurofibrillary tangles, two pathological hallmarks of AD. Aβ aggregates were found to be toxic both in vitro and in vivo. Numerous studies have shown that Aβ aggregates, especially soluble oligomers, impair both synaptic function and structure (Kokubo et al., 2005; Wilcox et al., 2011). Injection of soluble Aβ42 oligomers directly isolated form AD cerebral cortex into healthy rats leads to impaired memory (Selkoe et al., 2016).
In addition, accumulation of Aβ oligomers can not only trigger AD-type tau hyperphosphorylation and cause neurotic dystrophy (Jin et al., 2011; Stancu et al., 2014; Jacobs et al., 2018), but also activate neuroinflammation (Park et al., 2018; Henstridge et al., 2019). Apolipoprotein E4, the greatest genetic risk factor for late-onset AD, impairs Aβ clearance and promotes Aβ accumulation in the brain (Carter et al., 2001; Wildsmith et al., 2013).
Along with tau, Aβ might be transmissible through the Aβ contaminants in cadaver-derived human growth hormone for the treatment of Creutzfeldt-Jakob disease (Duyckaerts et al., 2018). From human genetics, dominant mutations causing early-onset familial AD reside either in APP or presenilin (catalytic sub-unit of γ-secretase), which alter the proteolytic processing of APP in ways either elevating the Aβ42/Aβ40 ratio or increasing the self-aggregation propensity of resultant Aβ peptides (De Jonghe, 2001; Selkoe, 2001; Chen et al., 2014). Duplication of the APP gene in Down’s syndrome leads to Aβ deposits in the teens, and almost invariably leads to AD at an early age (Lejeune et al., 1959; Head et al., 2012).
Interestingly, three DS patients with partial trisomy that excludes the APP gene did not develop dementia (Korbel et al., 2009; Doran et al., 2016). The human genetics of DS strikingly demonstrates that increasing Aβ dosage (APP duplication) causes dementia, while normalized Aβ dosage in DS (partial trisomy without APP duplication) prevents dementia (albeit the sample size = 3 is low), affirming that amyloid reduction is a fundamentally sound strategy for disease-modifying treatment of AD. The failures of anti-amyloid clinical trials in recent years can be attributed to giving the therapy too late to the patients, poor clinical trial design, heterogeneity of the trial patient population etc.
Aβ is a small peptide generated by proteolytic processing of APP (Figure 1A), a type-I transmembrane protein with a large extracellular domain. APP is transported to the plasma membrane through the endoplasmic reticulum -Golgi secretory pathway. The majority of APP is processed via the non-amyloidogenic pathway at the plasma membrane (Figure 1A). In the non-amyloidogenic pathway, APP is cleaved by α-secretase within the Aβ domain between Lys16 and Leu17, producing a soluble N-terminal fragment (APPs α) and a membrane-bound C-terminal fragment, C83, which can be further cleaved by γ-secretases and generates a soluble extracellular p3 peptide, thus precluding the formation of intact Aβ (Figure 1A; Anderson et al., 1991; Sisodia, 1992; Wilson et al., 1999).
Unlike the non-amyloidogenic pathway, APP is internalized and delivered to endosomes in the amyloidogenic pathway (Bu, 2009). During amyloidogenic APP processing, APP is cleaved by β-secretase (BACE1, β-site APP-cleaving enzyme 1), generating a soluble N-terminal fragment (APPsβ) and a membrane-bound C-terminal fragment (C99) (Vassar, 2004; Vassar et al., 1999). Within the membrane, C99 is subsequently cleaved by an enzymatic complex known as γ-secretase, releasing a cytoplasmic polypeptide termed AICD (APP intracellular domain) at the luminal side and Aβ peptides (Thinakaran and Koo, 2008) at the other side of the membrane.
AICD is transferred to the nucleus, where it functions as a transcriptional factor (Berridge, 2010), whereas the Aβ peptides are secreted into the extracellular space when the endosome recycles to cell surface. γ-Secretase cleaves APP at variable sites within the transmembrane domain, generating Aβ peptides ranging in length from 38 to 43 residues (Selkoe and Wolfe, 2007). Among different Aβ species, Aβ42 and Aβ43 are highly self-aggregating, while Aβ40 and shorter peptides are relatively benign (Burdick et al., 1992).
Aβ42 and Aβ40 are the two common Aβ species in the human brain and the increased Aβ42/Aβ40 ratio is a common biochemical feature in the early-onset familial AD (FAD) caused by mutations in APP and presenilin. Aβ42 aggregates rapidly into neurotoxic oligomers, leading to fibrils and plaques. It has been proposed that Aβ oligomers are more toxic than fibrils, therefore it may play a more important role than amyloid plaque in AD progression.
Aberrant process of APP by β-secretase and γ-secretase may result in imbalance between production and clearance of Aβ peptides, leading to toxic oligomers, fibrils and senile plaques. Interestingly, pathogenic mutations in presenilin were found to destabilize γ-secretase-APP interactions and thus enhance the production of longer Aβ peptides (Chévez-Gutiérrez et al., 2012; Veugelen et al., 2016; Szaruga et al., 2017). These finding points to enhancing the stability of γ-secretase-Aβn complex as a potential therapeutic approach for AD.
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418514/
More information: Andrea Sturchio et al, High cerebrospinal amyloid-β 42 is associated with normal cognition in individuals with brain amyloidosis, EClinicalMedicine (2021). DOI: 10.1016/j.eclinm.2021.100988