Why does Alzheimer’s disease (AD) risk increase with aging? Current AD therapy focuses on the removal of senile plaque amyloid that contains fibrils aggregated from the small protein amyloid beta peptide. Our new data show that brain levels of the small, soluble amyloid peptide increase in mice during normal aging, two months to 20 months. These findings verify a neglected study of normal human brains from Harvard indicating that the small amyloid peptide also increases exponentially across middle age, without AD pathology (Fukomoto et al., 2004). We hypothesize that the progressive elevations of small amyloid peptides trigger aggregation into the amyloid fibrils of senile plaque. For example, in Down syndrome, which has an extra copy of the amyloid gene, the excess soluble amyloid causes amyloid aggregation prematurely, a decade earlier than normal aging. Thus, AD may be considered a long-term process beginning with gradual elevations of the amyloid peptide much earlier than commonly appreciated in young adults. Long-term term treatment with drugs to decrease brain amyloid production may be considered, which may include BPN15606, designed by CureAlz scientists to modulate the enzymes that produce the amyloid peptide from its precursor protein.
The drug BPN15606 initially was studied as a potential protection from air pollution (AirPoll), which increases AD risk. Previously, we showed that rodents exposed to AirPoll have increased amyloid peptide production and larger amyloid plaques (Cacciottolo et al., 2017, 2020). In years one and two, BPN15606 did give some protection to mice from AirPoll neurotoxicity that decreases formation of new neurons in some brain regions and brings on the activation of microglial cells. Single-cell studies of messenger RNA show that BPN attenuated AirPoll impairment of neurogenesis in adult brains. These studies are the first to examine neurogenesis aging in relation to age increases of amyloid peptides, with or without exposure to AirPoll. These findings suggest a broader role for anti-amyloid drugs in protecting from AirPoll. Unexpectedly, BPN15606 also modified levels of neuronal proteins that included proteins at the synapse and several enzymes that generate amyloid peptides. Together with the above findings of early age increases of the amyloid peptide, these outcomes raise the possibility that the amyloid peptide regulates some normal function of synapses in healthy middle-age people.
Environmental factors in Alzheimer’s disease (AD) are poorly defined. Recent epidemiological studies strongly associate elevated air pollution (AirPoll) with increased risks for accelerated cognitive loss and AD. We hypothesized that AirPoll impairs neuron replacement in adults, which we confirmed in experiments with mice exposed to AirPoll, which impaired proliferation of neural stem cells (NSC). Maintenance of NSC in older ages is hypothesized as critical for resistance to AD-related pathology and cognitive deficits.
This CureAlz project investigates the molecular pathways of NSC impairments by AirPoll and their relation to brain amyloid peptides believed to drive AD. In Year 1 of this project, we showed that AirPoll damage to NSC is attenuated by an anti-amyloid drug developed by CureAlz investigators and with CureAlz support, BPN-15606. Specifically, single cell studies of messenger RNA show that BPN-15606 attenuates AirPoll impairment of neurogenesis in adult brains. These pathways will be analyzed in Year 2 for targets that may protect against AD risk from AirPoll. These studies are the first to examine NSC aging at the single cell level for modulation by AirPoll, and for environmental interactions with amyloid peptides. The findings could extend benefits of BPN-15606 and other anti-amyloid drugs to lowering environmental risks of AD.
Moreover, we showed that amyloid beta peptides, amyloid beta 40 and amyloid beta 42, increase sharply after brain maturation in normal mice. This finding parallels the exponential midlife increase of amyloid beta 40 and amyloid beta 42 in aging humans in a rigorous but neglected study by Fukumoto et al., published in the American Journal of Pathology in 2004. Normal brain aging in mice and humans thus increases amyloid beta peptides, which may predispose humans to AD.