Aβ1-6A2V(D) peptide, effective on Aβ aggregation, inhibits tau misfolding and protects the brain after traumatic brain injury

Abstract

Alzheimer’s disease (AD), the leading cause of dementia in older adults, is a double proteinopathy characterized by amyloid-β (Aβ) and tau pathology. Despite enormous efforts that have been spent in the last decades to find effective therapies, late pharmacological interventions along the course of the disease, inaccurate clinical methodologies in the enrollment of patients, and inadequate biomarkers for evaluating drug efficacy have not allowed the development of an effective therapeutic strategy. The approaches followed so far for developing drugs or antibodies focused solely on targeting Aβ or tau protein. This paper explores the potential therapeutic capacity of an all-D-isomer synthetic peptide limited to the first six amino acids of the N-terminal sequence of the A2V-mutated Aβ, Aβ1-6A2V(D), that was developed following the observation of a clinical case that provided the background for its development. We first performed an in-depth biochemical characterization documenting the capacity of Aβ1-6A2V(D) to interfere with the aggregation and stability of tau protein. To tackle Aβ1-6A2V(D) in vivo effects against a neurological decline in genetically predisposed or acquired high AD risk mice, we tested its effects in triple transgenic animals harboring human PS1(M146 V), APP(SW), and MAPT(P301L) transgenes and aged wild-type mice exposed to experimental traumatic brain injury (TBI), a recognized risk factor for AD. We found that Aβ1-6A2V(D) treatment in TBI mice improved neurological outcomes and reduced blood markers of axonal damage. Exploiting the C. elegans model as a biosensor of amyloidogenic proteins’ toxicity, we observed a rescue of locomotor defects in nematodes exposed to the brain homogenates from TBI mice treated with Aβ1-6A2V(D) compared to TBI controls. By this integrated approach, we demonstrate that Aβ1-6A2V(D) not only impedes tau aggregation but also favors its degradation by tissue proteases, confirming that this peptide interferes with both Aβ and tau aggregation propensity and proteotoxicity.

Translating from mice to humans: using preclinical blood-based biomarkers for the prognosis and treatment of traumatic brain injury

“…All drugs had demonstrated neurotherapeutic effects in preclinical studies based on other neurological, biochemical, and histological outcome measures. Of these, Aβ1-6A2V(D) and DHA reported a decrease TBI-induced blood NfL levels following drug treatment (51,53), while the other two drugs (Immunocal, LEV) did not (41,54).…”

“…In moderate-to-severe TBI models, 2 studies assessed NfL levels within 0-24 hours (h) of injury (’hours’, (36,47), 6 studies from 1 to 6 days (d) (‘days’, (7,39–41,51,52)), 3 studies from 1 to 4 weeks (w) (‘weeks’, (7,40,53)), and only 1 study assessed NfL at months (m) post-injury (’months’, (37)) ( Fig. 4A ).…”

“…The pharmacodynamic value of circulating NfL was assessed in four preclinical drug treatment studies (41,51,53,54). Drugs tested included a) Aβ1-6A2V(D), an all-D-isomer synthetic peptide that interferes with the aggregation and stability of tau protein (51); b) Immunocal, a cysteine-rich whey protein supplement and glutathione precursor (54); c) levetiracetam (LEV), an anti-seizure medication (41); and d) docosahexaenoic acid (DHA), a neuroreactive omega-3 fatty acid (53). All drugs had demonstrated neurotherapeutic effects in preclinical studies based on other neurological, biochemical, and histological outcome measures.…”

Recent insights from non-mammalian models of brain injuries: an emerging literature

“…Sea lampreys have also been used to study the movement and deposition of tau and its subsequent role in neurodegeneration. One study demonstrated that mutated tau, particularly the P301L form, migrates in a transneuronal manner, while wild-type tau does not ( 114 , 115 ). Another study showed that extracellular human tau moves both synaptically and non-synaptically ( 116 ).…”

“…Surprisingly, when naive mice were intracerebrally inoculated with tau TBI , a prion-like spread of tau TBI occurred, resulting in memory deficits and synaptic toxicity ( 131 , 132 ). Moreover, Diomede et al established the therapeutic potential of Aβ1-6A2V(D), an all-D-isomer synthetic peptide, to promote tau degradation by proteases and impede tau aggregation in a C. elegans model ( 114 ). Additionally, the average lifespan of C. elegans ranges from 9 to 23 days depending on the rearing temperature ( 133 ), highlighting the ability to track tau aggregation through the entire lifespan of the organism.…”