New research led by North­eastern Uni­ver­sity sug­gests that Alzheimer’s dis­ease may not progress like falling domi­noes, as con­ven­tional wisdom holds, with one mol­e­c­ular event sparking the for­ma­tion of plaques throughout the brain. Instead, it may progress like a fire­works dis­play, with a unique flare launching each plaque, one by one.

The study, headed by Lee Makowski, pro­fessor and chair of the Depart­ment of Bio­engi­neering, was pub­lished Thursday in the journal Sci­en­tific Reports.

I believe the find­ings will pro­vide us with a new way of thinking about the mol­e­c­ular basis for Alzheimer’s dis­ease pro­gres­sion,” says Makowski. “Once you do that, you can start asking the right ques­tions about how to pre­vent it.”

Dis­tin­guishing between the fib­rils may pro­vide crit­ical insights for devel­oping ther­a­pies to slow, halt, or reverse the neu­rode­gen­er­a­tion asso­ci­ated with Alzheimer’s dis­ease.
—Lee Makowski

More than 5 mil­lion Amer­i­cans are living with Alzheimer’s dis­ease, according to the Alzheimer’s Asso­ci­a­tion. It is the sixth leading cause of death in the U.S., the asso­ci­a­tion reports, killing more people than breast and prostate can­cers combined.

Yet much about its cause and the mech­a­nisms dri­ving its pro­gres­sion remain unknown. Alzheimer’s dis­ease typ­i­cally starts with the death of brain cells, or “neu­rons,” in one part of the brain and then, over time, slowly spreads to other regions. Amy­loid fibrils—thin rigid strands of pro­tein aggregates—accumulate in these areas of neu­ronal death, packing together to form dense plaques.

Just as there are dif­ferent strains of a virus, there appear to be dif­ferent strains of fib­rils,” explains Makowski. “Remark­ably, the dif­ferent strains have the same chem­ical makeup but dif­ferent three-​​dimensional structures.”

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Insight into therapies

It was the struc­tures that Makowski’s team zeroed in on.

In col­lab­o­ra­tion with researchers from Mass­a­chu­setts Gen­eral Hos­pital and Argonne National Laboratory’s Advanced Photon Source, Makowski and former research asso­ciate Jil­iang Liu, PhD’15, scanned slices of brain tissue retrieved at autopsy from four people with Alzheimer’s and one with no his­tory of dementia using an X-​​ray beam just five microns across. They then built images of the fibrous struc­tures within the plaques from the thou­sands of dif­frac­tion pat­terns they collected.

Because fib­rils self-​​propagate, researchers have spec­u­lated that all fib­rils in a given brain are of the same strain and hence have the same struc­ture. That led to the assump­tion that a single mol­e­c­ular event ini­ti­ated their accu­mu­la­tion into plaques and the sub­se­quent cas­cading pro­gres­sion of the disease.

Our data wasn’t con­sis­tent with that,” says Makowski. “We found that fib­rils with dis­tinctly dif­ferent struc­tures can accu­mu­late in the same brain, even in plaques quite close to one another. This strongly sug­gests that there is not one event that ini­ti­ates fibril for­ma­tion throughout the brain but many. Our research indi­cates that it is the con­di­tion under which fib­rils form that slowly prop­a­gates through the brain and trig­gers a dis­tinct ini­ti­a­tion event for each plaque.”

Think of a cold front trav­eling south from Mass­a­chu­setts to Vir­ginia. It’s raining up and down the East Coast. When con­di­tions are right in Massachusetts—that is, when the tem­per­a­ture drops to 32 degrees—the rain turns to snow (the ini­ti­a­tion event). Vir­ginia, how­ever, doesn’t get any snow until a week later when its tem­per­a­ture drops to the freezing point. As in the brain, the con­di­tions drive the event.

The find­ings are impor­tant because they change the way we think about dis­ease pro­gres­sion,” says Makowski. “It gives us a new point of view from which to develop hypotheses about the con­di­tions that lead to the for­ma­tion of fib­rils and plaques.”

The researchers also showed that the struc­ture of the fib­rils may vary based on a person’s clin­ical his­tory. For example, the fib­rils of one woman who had exhib­ited no signs of dementia prior to death were dis­tinctly dif­ferent from those found in the others, who had Alzheimer’s disease.

This may mean that some strains of fib­rils are asso­ci­ated with dis­ease whereas others are not,” says Makowski. “Dis­tin­guishing between them may pro­vide crit­ical insights for devel­oping ther­a­pies to slow, halt, or reverse the neu­rode­gen­er­a­tion asso­ci­ated with Alzheimer’s disease.”


Source: Northeastern University