Association of accelerated long-term forgetting and senescence-related blood-borne factors in asymptomatic individuals from families with autosomal dominant Alzheimer’s disease

Abstract

Background Accelerated long-term forgetting has been identified in preclinical Alzheimer’s disease (AD) and is attributed to a selective impairment of memory consolidation in which the hippocampus plays a key role. As blood may contain multiple senescence-related factors that involved in neurogenesis and synaptic plasticity in the hippocampus, we tested whether there is an association between blood-borne factors and accelerated long-term forgetting in asymptomatic individuals from families with autosomal dominant AD (ADAD). Methods We analyzed data of 39 asymptomatic participants (n = 18 ADAD mutation carriers, n = 21 non-carriers) from the Chinese Familial Alzheimer’s Disease Network (CFAN) study. Long-term forgetting rates were calculated based on recall or recognition of two materials (word list and complex figure) at three delays comprising immediate, 30 min, and 7 days. Peripheral blood concentrations of candidate pro-aging factors (CC chemokine ligand 11 [CCL11] and monocyte chemotactic protein 1 [MCP1]) and rejuvenation factors (growth differentiation factor 11 [GDF11], thrombospondin-4 [THBS4], and secreted protein acidic and rich in cysteine like 1 [SPARCL1]) were evaluated in all participants. Results Despite normal performance on standard 30-min delayed testing, mutation carriers exhibited accelerated forgetting of verbal and visual material over 7 days in comparison with matched non-carriers. In the whole sample, lower plasma THBS4 was associated with accelerated long-term forgetting in list recall (β = −0.46, p = 0.002), figure recall (β = −0.44, p = 0.004), and list recognition (β = −0.37, p = 0.010). Additionally, higher plasma GDF11 and CCL11 were both associated with accelerated long-term forgetting (GDF11 versus figure recall: β = 0.39, p = 0.007; CCL11 versus list recognition: β = 0.44, p = 0.002). Conclusions Accelerated long-term forgetting is a cognitive feature of presymptomatic AD. Senescence-related blood-borne factors, especially THBS4, GDF11, and CCL11, may be promising biomarkers for the prediction of accelerated long-term forgetting.

Blood-to-brain communication in aging and rejuvenation

“…This work revealed two factors capable of promoting synaptogenesis and dendrite arborization: the secreted matricellular proteins thrombospondin 4 (THBS4) and SPARC-like protein 1 (SPARCL1) 115 . Interestingly, lower plasma levels of THBS4 were found to be associated with impaired long-term recall in asymptomatic middle-aged humans from families with autosomal dominant AD 116 . However, it is unknown whether THBS4 or SPARCL1 are beneficial when administered systemically or whether they can cross the BBB to act directly on neurons.…”

Growth differentiation factor 11 promotes macrophage polarization towards M2 to attenuate myocardial infarction via inhibiting Notch1 signaling pathway

“…To date, studies of the GDF11 have focused on aging, embryonic development, and bone formation and GDF11 plays a critical role in the occurrence and development of various diseases [26][27][28][29][30] . GDF11 has shown significant anti-inflammatory effects on inflammatory diseases such as rheumatoid arthritis [16] and ulcerative colitis [15] .…”

“Focused Ultrasound-mediated Drug Delivery in Humans – a Path Towards Translation in Neurodegenerative Diseases”

“…Currently, successful clinical trials report opening of >1 cm 3 of human BBB [43,44], which given widespread pathology observed in neurodegenerative diseases, may not be sufficient to achieve meaningful therapeutic outcomes. However, since FUS+MB has been shown to induce proinflammatory responses in animal models [98] and age-associated blood-borne factors could be detrimental if entering the brain in excessive amounts [99,100], opening of the BBB in the entire brain as achieved in FUS-scanning mode in mouse models [20,92,101] can have adverse effects for the patient.…”